Zito would go on to win the AL Cy Young Award with a 23–5 record, narrowly defeating Pedro Martínez in the voting. He led the league with 23 wins, was second in winning percentage (.821), and third in both ERA (2.75) and strikeouts (182). Zito’s 23 wins were the most by an AL left-hander since Frank Viola had 24 wins for Minnesota in 1988. Zito also allowed a .185 average to opposing hitters, the lowest in the AL. Martínez, who had led the AL in ERA (2.26), strikeouts (239), and winning percentage (.833), became the first pitcher since the introduction of the award to lead his league in each of the three categories and not win the award. Zito became the first A’s pitcher to win the Cy Young Award since Dennis Eckersley did it in 1992. Zito was also named AL TSN Pitcher of the Year.

Zito also played in the Cape Cod Baseball League, a summer wooden bat league which showcases the nation’s top amateur prospects. He led the Wareham Gatemen to the league championship in 1997, and a runner-up finish in 1998.

Zito was taken by the Seattle Mariners in the 59th round (1,586th overall) of the 1996 Major League Baseball (MLB) draft, and in the third round (83rd overall) by the Texas Rangers in 1998, but did not sign with either team. In the 1999 draft, he was selected by the Oakland Athletics with the ninth pick of the first round, and signed for a $1.59 million bonus.

In 1999, Zito began his professional career with the Visalia Oaks, Oakland’s A team. He went 3–0 with a 2.45 ERA in eight starts. He struck out 62 in 40 ⁄3 innings. Zito was promoted to the Midland RockHounds, and went 2–1 with a 4.91 ERA to finish the AA schedule. He then got one start for the AAA Vancouver Canadians (PCL), allowing a lone run with six strikeouts in six innings.

Zito started playing guitar in 1999 as a way to pass time on road trips. He had not considered music as a profession until his sister, Sally Zito, asked him to play guitar in her band with which he played during the offseason from 2000 to 2007. It was then that he began writing songs in preparation for a career after baseball. His 2015 comeback bid found him playing the majority of the season in Nashville, Tennessee, the home of country music. He used his time off to learn from the city’s music industry professionals and to pursue songwriting. Zito released his first EP, titled No Secrets, on January 27, 2017. The collection contains six songs either written or co-written by Zito. He later co-wrote and sang vocals for a theme song for the Nashville Sounds, titled “That Sound”.

Zito made his major league debut on July 22, 2000, against the Anaheim Angels wearing #53. He allowed one run in five innings, and got the win. In his next start, Zito went seven innings while giving up three runs to the Boston Red Sox. Zito continued to have great success early in his rookie season. In his third career start, he went seven innings and gave up one run against the Toronto Blue Jays. On September 10, Zito pitched his first complete game shutout against the Tampa Bay Devil Rays. He threw 110 pitches, struck out eight, and allowed five hits. During the month of September, he went 5–1 with a 1.73 ERA. Zito finished with a 7–4 record and a 2.72 earned run average in 14 starts. Despite his late start to the season, Zito still finished fifth in American League (AL) Rookie of the Year Award voting.

From 2000 through 2004 with the Athletics, Zito, Hudson, and Mulder were known as the “Big Three.” Of the three, Zito had the highest single-season win total and was the only one to win the Cy Young Award. Zito’s .618 winning percentage is 10th all-time in Athletics history. His 6.896 strikeouts per 9 innings pitched ranks seventh, his 1,096 strikeouts rank eighth, and his 222 games started rank 10th. Zito also holds a couple more dubious positions on Oakland’s list: his 148 home runs allowed rank fifth, and his 65 hit by pitches rank fourth (although he trails Eddie Plank, Chief Bender, and Rube Waddell in that category). Zito’s .821 winning percentage in 2002 is tied with Bender’s in 1910 for 10th among Athletics’ single-season totals. His 8.608 strikeouts per 9 innings pitched in 2001 rank seventh, and his 205 strikeouts in 2001 are tied for 10th (with Dave Stewart’s 1987 total and Todd Stottlemyre’s 1995 total).

In 2001, Zito Switched his uniform number to 75 (which he would wear throughout the rest of his career) finished third in the American League (AL) in strikeouts per nine innings (8.61), fourth in strikeouts (205), sixth in wins (17), eighth in ERA (3.49), and tenth in winning percentage (.680). Zito became the sixth lefty aged 23 or younger since 1902 to strike out at least 200 batters in a season. After a great rookie season, Zito struggled through the early part of the 2001 season, posting a 6–7 record with a 5.01 ERA in his first 22 starts. However, he rebounded nicely and by August, he was putting up good pitching numbers. Zito was named Pitcher of the Month in August, going 5–1 with a 1.02 ERA. Zito won Pitcher of the Month again in September, going 6–0 with a 1.89 ERA. During those last two months of the season, Zito went a combined 11–1 with a 1.32 ERA, best in baseball.

In 2002, Zito became one of the best pitchers in baseball. On June 22, Zito won his 10th game of the season. It was the earliest that an A’s pitcher had reached the 10-win mark since Bob Welch got there on June 15, 1990. Zito was named to the All-Star team for the first time in his career. On July 18, he went 7.1 innings while giving up no runs against the Angels. That win gave Zito a team-record 16th straight win at home. Zito again faced the Angels in his next start and produced similar results. He went 6.1 innings and gave up just one run. That win gave Zito the most wins by an AL pitcher (14). Zito would become the AL’s first 15-game winner when he beat the Rangers. On August 23, Zito recorded his 18th win of the season, giving him one more than his previous career high of 17, in a game against the Detroit Tigers.

In 2003, Zito started off with a win against the Mariners. He went 6 innings and allowed an earned run, an RBI single by Olerud in the first inning. In his next start, Zito went 7 innings, struck out 7, walked 4, and allowed one run against Texas. In the process, he became only the fifth A’s pitcher to win 10 straight games, the first since Welch in 1990. On April 18, Zito went nine innings, allowing six hits and no runs in a start against the Rangers. Zito improved to 9–0 in his career against Texas. After the game, Texas manager Buck Showalter said, “I got the feeling he made it look pretty easy. When he has that kind of command, you can see what happens.” Zito struggled in his second-to last start before the All-Star Break on July 8. He allowed seven earned runs and 15 hits against the Devil Rays. The 15 hits allowed were a career high. Devil Rays manager Piniella was stunned by Zito’s bad start. He said, “If you’d have told me we’d get 15 hits off Zito in five or six innings, I would have looked at you a little funny.” Nevertheless, Zito bounced back in his next start. He went eight innings without surrendering a run against the Baltimore Orioles. Zito was again named to the All Star team, the second time he has been named to the team.

In 2003, Zito was seventh in the AL in ERA (3.30). He had a 14–12 record and 146 strikeouts over a career-high 231 ⁄3 innings pitched.

In 2003, Zito portrayed a United States Navy petty officer in an episode of JAG on CBS. Zito’s character, a pitcher, faced assault charges after hitting a Marine with a ball during the annual Navy-Marine all-star baseball game.

In 2004, Zito struggled and posted the worst numbers of his career at the time. Zito went 2–3 with a 6.83 ERA in the month of April. On May 28, facing Cliff Lee, he threw eight shutout innings but received a no-decision in a 1–0 loss to the Cleveland Indians. He threw eight shutout innings of four-hit ball in a 5–0 victory over the Devil Rays on August 21. Oakland manager Ken Macha would have let him throw a complete game, but Zito said, “I was worrying about being fresh for the next game. I didn’t want to end up [throwing] 115–120 [pitches], so I took advantage of the situation and shut it down.” On September 12, he threw seven shutout innings and had 10 strikeouts, earning the win in a 1–0 victory over the Indians. For the season, he went 11–11 with a 4.48 ERA. That was his only year with the Athletics that his ERA was more than 4.00. He still finished 10th in the league in strikeouts with 163.

Following the departure of Tim Hudson and Mark Mulder, Zito was given his first Opening Day assignment in 2005. He allowed four runs over six innings in a 4–0 loss to the Orioles on April 4. In 2005, Zito again struggled in the month of April, going 0–4 with a 6.60 ERA. In his first 16 starts of the campaign, he was 3–8 with a 4.41 ERA. However, Zito pitched better the rest of the season. He had a streak of 14 consecutive starts from May 17 through July 25 (and 20 out of 21 through August 30) in which he gave up fewer hits than innings pitched. From June 28 through August 4, he earned the win in eight consecutive starts. On June 6, Zito allowed two runs in six innings in a 2–1 loss to the Washington Nationals. During the game, he collected his first major league hit, against Tony Armas, Jr.. Zito was named Pitcher of the Month in July, going 6–0 with a 2.51 ERA. In 35 starts, Zito went 14–13 with a 3.86 ERA. Zito’s 35 starts were the most in Major League Baseball that season, demonstrating his durability as a pitcher. He also had 171 strikeouts, good for fifth in the league.

Zito’s fastball has hovered between 84 miles per hour (135 km/h) and 88 miles per hour (142 km/h). He augments it with a circle changeup and a curveball that he uses as a strikeout pitch. His curveball was voted the best in the Major Leagues in a player poll conducted by Sports Illustrated in 2005. Alex Rodriguez once stated that he had never seen anything like Zito’s curveball, commenting: “It’s such a high one, and it drops three to four feet. You might as well not even look for it because you’re not going to hit it.”

In 2006, Zito went 1.1 innings and allowed seven earned runs on Opening Day (April 3) against the Yankees. It was the shortest outing of his career. However, Zito quickly rebounded from that bad start. On June 1, he allowed four hits over seven innings in a 4–0 victory over the Twins. During the game, he recorded his 1,000th career strikeout by punching out Lew Ford. On July 2, Zito and Brandon Webb both allowed one run through eight innings before Zito gave up two unearned runs while only getting two outs in the ninth; Webb threw a complete game as the Arizona Diamondbacks beat the Athletics 3–1. When the All-Star Break rolled around, Zito was 8–6 with a 3.29 earned run average. He was named to the 2006 All-Star Game. On August 25, Zito earned his 100th career win when he defeated the Rangers 9–3. He had a no-hitter going into the eighth inning, but Mark DeRosa singled to lead it off. In 35 starts (first in the league again), he had a 16–10 record, a 3.83 ERA, and 151 strikeouts. Zito was tied for eighth in the league in wins, he ranked tenth in ERA, and he was third in innings pitched (221). He had the eighth-lowest run support of AL pitchers (4.97) but had a 15–1 record if he received at least two runs of support.

Zito replaced his agent Arn Tellem with Scott Boras in July 2006. Zito was a focal point of the 2006 trade deadline, and was widely rumored to be headed to the Mets in a potential deal for prospect Lastings Milledge. Susan Slusser of the San Francisco Chronicle wrote that if the Mets were unwilling to trade Milledge, the Athletics might be interested in Aaron Heilman and John Maine. However, Athletics’ general manager Billy Beane decided to keep Zito for the rest of the season.

Following his seventh season with the Athletics, Zito signed a seven-year deal with the San Francisco Giants worth $126 million, plus $18 million option for 2014 with a $7 million buyout. Zito’s contract on December 29, 2006, became the highest for any pitcher in Major League history at the time.

During spring training in 2007, he and Barry Bonds made shirts that read “Don’t ask me, ask Barry” with an arrow pointing to the other Barry. By all accounts, Zito and Bonds got along well during their short time as teammates, and Zito made a point of saying he would stand by Bonds through onslaughts from the media.

Zito was raised in a “spiritual, metaphysical type church” that was founded by his grandmother and that his mother, Roberta, who died in 2008, formerly preached at. In 2001, Zito espoused a universal life force that he credited with his midseason turnaround. He said that he discovered this force by reading Creative Mind by Ernest Holmes.

The 2009 season seemed to mark a rebound in Zito’s pitching performance. Though starting the season 0–2 with an ERA of 10, Zito ended the season with an ERA of 4.03. His ERA would have been 3.74 had it not been for his first two starts. Though going only 10–13 in the season, Zito’s record was much more the fault of his spotty run support (the second-lowest in the major leagues) than his performance on the mound. On June 21, Zito pitched a no-hitter through six innings against Texas before giving up a home run to Andruw Jones in the seventh inning. He won the game, his fourth win of the season. On July 7, Zito pitched what could be considered his best game of the season. He pitched 8⁄3 innings against the Florida Marlins, allowing one run on four hits, striking out six, and walking one. He won the game, his fifth win of the season.

Since mid-2004, Zito has added a two-seam fastball and a cutter–slider hybrid to his arsenal. In the 2009 season, this cutter-slider became a prominent part of his repertoire, being used more frequently than his changeup. Zito’s diminished velocity at the start of the 2007 season (his fastball velocity slowed to 83–85 miles per hour (134–137 km/h)) and loss of command were the key mechanical reasons for his struggles that year, as he more often got behind in the count and had to rely more on his fastball. During the 2009 season, Zito made changes to his delivery, lowering his arm slot from an over the top angle to a three quarters delivery. This change helped his fastball velocity go back up to the 86–89 miles per hour (138–143 km/h) range as well as sharpening the break of his curveball. However, in 2011, he was once again in the 84–87 miles per hour (135–140 km/h) range with his fastball. In 2012, Zito relied mostly on his two-seam fastball and cutter, and reduced his reliance on the four-seamer, which was the slowest four-seamer in MLB among starting pitchers that year, at 84.6 miles per hour (136.2 km/h).

Zito started the 2010 season by pitching six shutout innings against the Houston Astros to earn a win; it was the first time he had won his season opening start since 2003. On April 24, Zito stifled the St. Louis Cardinals, throwing eight shutout innings with ten strikeouts for his third victory of the season, en route to starting the season 5–0 for the first time in his career. It was the best start by a Giants’ pitcher since 2004, when Lowry started 6–0. On June 12, 2010, Zito earned his first win against his former team, the Athletics, which gave him victories against every MLB team. Zito is one of eighteen pitchers to record a win against all 30 MLB teams, and the first pitcher to accomplish the feat while only with two clubs

Zito’s regular season performance with the Giants was less successful; he went 63–80 with a 4.62 ERA. However, he had significantly more playoff success with them. Aided by his contributions in 2010, the team won its first World Series since 1954. Zito did not pitch in the playoffs that year, but did pitch in the 2012 postseason, saving the Giants’ season by pitching them to a Game 5 victory in the NLCS against the Cardinals, and then outdueling Tigers’ ace Justin Verlander in Game 1 of the 2012 World Series. The Giants went on to win their second World Series in three years.

Zito founded the charity Strikeouts For Troops. The charity provides comforts of home and works to lift the spirits and morale of injured US troops and offers support to military families. In 2010, Zito announced that he would donate $1,500 for every strikeout in the Giants–Padres game on September 11. There were a total of 14 strikeouts in the game.

Early in the 2011 season Zito experienced his first trip to the disabled list after an injury to his right foot during a fielding play. His replacement, Ryan Vogelsong, excelled, but Zito was able to rejoin the rotation when he returned in June because Sánchez was placed on the disabled list with left biceps tendinitis. Zito pitched well in his first few starts back, pitching well against the Tigers, Chicago Cubs, and Padres en route to three Giants wins, but later resumed his struggle, going 0–3 with a 10.91 ERA over his next three starts. He returned to the disabled list after aggravating his right foot injury; ironically, his trip to the DL made room for Sánchez to return to the rotation. On August 13, Zito injured his right ankle on another fielding play in a Triple-A rehab start, sidelining him for another month. Zito returned from the DL on September 11 but was used out of the bullpen for the rest of the year; he posted a 9.00 ERA over his final four games. In a career-low 13 games (nine starts), he had a 3–4 record, a career-high 5.87 ERA, 32 strikeouts, and 24 walks in a career-low 53 ⁄3 innings.

Zito became engaged to former Miss Missouri Amber Seyer in April 2011, and they were married on December 3, 2011. His father, Joe Zito, who died June 19, 2013, at the age of 84, composed and arranged music for Nat King Cole in the early 1960s (ca.1961–64) and arranged for the Buffalo Symphony Orchestra. Zito’s mother Roberta was a musician who sang in a choral group known as The Merry Young Souls and with Nat King Cole and his band. Zito is also a musician. He plays guitar, and he co-wrote the song “Butterflies” that was used in the Eddie Murphy film A Thousand Words. Zito’s uncle is television actor Patrick Duffy, who was married to his maternal aunt.

However, in August 2011, Zito became a Christian, saying he “committed to Jesus Christ as his Lord and Savior.” Zito explained that God got his attention through his being left off the 2010 Giants postseason roster and a car accident and freak foot injury in early 2011. He got a tattoo (his only one) of a golden calf on the inside of his right bicep as a reminder for him to “not worship false idols” and to remember that God comes first. Zito said that his wife is a Christian as well. In 2019, Zito wrote Curveball: How I Discovered True Fulfillment After Chasing Fortune and Fame ( ISBN 0785227881), a memoir book about his life and his conversion to Christianity. Zito has said, “Having placed my full identity into my baseball career for most of my life, only to have it stripped away during the 2010 World Series run is what led me to discover my true identity. Not in a game, but in Jesus Christ.”

Zito faced off against the Reds in Game 4 of the National League Division Series (NLDS) on October 10 and struggled, being pulled in the third inning after allowing two runs. However, the Giants went on to win 8–3. The Giants, after losing the first two games of the series, became the first team to rally from a 2–0 deficit in an NLDS, winning the series in five games. On October 19, 2012, Zito rebounded and pitched arguably the best game of his career, tossing 7⁄3 shutout innings against the St. Louis Cardinals in Game 5 of the National League Championship Series (NLCS), earning the win. It was his first postseason win since 2006 and according to Zito himself, was the biggest win of his career. That same day, Zito inspired the Twitter hashtag #rallyzito, which, behind the efforts of Giants fans, was trending worldwide on the social networking site. The Giants, after trailing 3–1 in the series, prevailed in seven games.

On October 24, 2012, Zito pitched in the first World Series of his career. As the Game 1 starter, Zito earned the win, outpitching Detroit’s Justin Verlander by tossing 5 2/3 innings of one-run ball. Zito also added an RBI single en route to an 8–3 Giants win. The Giants went on to sweep the Tigers in the World Series, and Zito went 2–0 with a 1.69 earned run average in the postseason. Zito did not lose a single game after August 2 against the Mets, and San Francisco won his last 14 starts.

On April 5, 2013, during the Giants’ home opener, Zito held the Cardinals scoreless over seven shutout innings, earning the 1–0 win. He followed this performance with seven more shutout innings and some personal offensive contribution at the plate against the Rockies in a 10–0 win to complete a 3-game series sweep. It was the Giants’ 16th straight victory in a row in games started by Zito (including the 2012 regular season and postseason), the longest such streak by a Giants pitcher since 1936 by Hall of Fame left-handed pitcher Carl Hubbell. However, Zito struggled for the rest of the season, going 2–10 with a 6.24 ERA after April 21 and losing his rotation spot a couple times late in the year.

Zito and wife Amber gave birth to their first child, a son named Mars, in July 2014. They adopted their second child, a son named Mercer Joseph Zito, in May 2017. A third child, a son named Rome, was born February 2020

After taking a year off from baseball, Zito signed a minor league contract to return to the Athletics on February 16, 2015. In spring training, Zito competed for a role on the Athletics’ 25-man roster, possibly as a long reliever. On April 4, 2015, Zito accepted an assignment to the Triple-A Nashville Sounds. Zito’s Nashville teammates lauded him for embracing the Triple-A lifestyle and for his commitment to the team: charting pitches between starts, coaching first base, and even buying dinner for the entire team on his birthday. Zito spent the entire season with Nashville, including about a month on the disabled list with left shoulder tendinitis. He was activated on the next-to-last day of the season on which he pitched one scoreless inning of relief. In a total of 24 appearances (22 starts), he accrued an 8–7 record with a 3.46 ERA and 91 strikeouts.

Zito revealed in an interview that he had learned the Athletics would not be bringing him up to the major league club in September. However, following a season-ending injury to Jesse Chavez, Oakland purchased Zito’s contract from Triple-A on September 16, placing him on the major league roster. Zito made his first major league appearance of the season on September 20, pitching an inning in relief. On September 26, 2015, Zito started for the Athletics against Hudson and the Giants in a matchup that was arranged as a tribute to the A’s “Big Three” of the early 2000s. Both pitchers received lengthy standing ovations from the sold-out Coliseum crowd (which included the third Big Three member, Mulder) upon leaving the game.

On October 19, 2015, Zito announced his retirement from baseball in an article for The Players’ Tribune.