Undrafted out of high school, Swisher enrolled at Ohio State University, as that school and Ohio University were the only colleges to recruit him for baseball. Playing for the Ohio State Buckeyes baseball team in the Big Ten Conference, Swisher was named Big Ten Freshman of the Year in 2000, after hitting .299 with 10 home runs and 48 runs batted in (RBI). In 2000, he played collegiate summer baseball with the Wareham Gatemen of the Cape Cod Baseball League. He was an All-Big Ten selection as a first baseman as a sophomore in 2001, after hitting .322 with 56 RBI and a league-leading 15 home runs. He earned All-Big Ten honors as an outfielder in 2002, after batting .348 with 10 home runs and 52 RBI.

Swisher was selected by the Oakland Athletics with a first round pick they received from the Boston Red Sox in 2002 as compensation for the signing of free agent Johnny Damon by the Red Sox. Swisher and the Athletics’ 2002 draft are heavily featured in Michael Lewis’ 2003 book Moneyball. In a book whose key theme is the gulf between orthodox baseball thinking and the new sabermetric-influenced system being implemented by Billy Beane, Swisher was notable as one of the few examples of a player who traditional scouts and Beane could agree upon.

Swisher made his professional debut with the Vancouver Canadians of the Class A-Short Season Northwest League in 2002, before he was promoted to the Visalia Oaks of the Class A-Advanced California League. Swisher started the 2003 season with the Modesto A’s, Oakland’s new California League affiliate, where he batted .296 in 51 games before receiving a promotion to the Midland RockHounds of the Class AA Texas League in June. He batted .230 in 76 games for Midland to finish the season, and then played in the Arizona Fall League for the Mesa Desert Dogs.

Swisher made his MLB debut in 2004 for the Athletics, playing in 20 games. Retaining his rookie status for 2005, Swisher hit 21 home runs and recorded 74 RBI in 131 games for the 2005 Athletics. He finished 6th in the American League Rookie of the Year voting. Teammate Huston Street won the award, while fellow 2002 Oakland draftee Joe Blanton finished seventh.

Swisher was very close to his paternal grandmother, Betty Lorraine Swisher, who raised him after his parents’ divorce. She died from brain cancer in 2005, and he has a memorial tattoo in her honor on his chest (her initials, surrounded by angel’s wings and a halo.) Swisher routinely looks up to the sky to honor his parents and grandparents. He also touches his lips and points to the sky in his grandmother’s honor after he gets a hit as well as inking her initials on the bottom of his bats’ knobs and kissing the letters when he comes to home plate. To honor her further, he let his hair grow for eleven months and donated it to Pantene Beautiful Lengths, a program that creates free wigs for cancer patients. On May 19, 2007, he cut his hair with assistance from his father. His website, nickswisher.net, is also dedicated to his grandmother. After his grandfather, Don, died in November 2008, Swisher began adding his initials to his bats as well. He later stated that he planned on getting another tattoo on his back in the same style as his existing one after the 2009 season to honor his grandfather.

Swisher made his postseason debut as the Oakland A’s took on the Minnesota Twins in the 2006 ALDS. Swisher got 3 hits and an RBI during the series as the Oakland A’s performed a 3-game sweep against the Twins to advance to the ALCS. During the 2006 ALCS vs the Detroit Tigers, Swisher had a .100 batting average with one hit. The Oakland A’s would eventually lose the ALCS to the Tigers in just 4 games.

On September 16, 2007, Swisher initiated a brawl when he charged the mound after getting hit by a pitch from Texas Rangers pitcher Vicente Padilla. Earlier in the plate appearance, Padilla (who had hit Swisher the prior year) threw two inside pitches with the apparent intention of hitting Swisher. Both players were ejected following the brawl, and Swisher received a three-game suspension.

Swisher was traded on January 3, 2008 to the Chicago White Sox for minor leaguers Ryan Sweeney, Gio González, and Fautino de los Santos as part of what Athletics general manager Billy Beane termed a “rebuilding effort”. While Swisher quickly established himself as a fan favorite on his new team he struggled offensively, batting just .219 through the season (the lowest batting average in the majors), though he improved his home run total from 22 in 2007 to 24 in 2008. He also led the majors in pitches per plate appearance, with 4.51. Because of his poor offensive play White Sox manager Ozzie Guillén benched Swisher for most of September, saying publicly that “I have to put the best lineup out there to win the game … To me, the best lineup right now is without (Swisher).” Swisher finished the 2008 regular season with a .219 batting average, 24 home runs, and 69 RBI.

On November 13, 2008, Swisher and minor league pitcher Kanekoa Texeira were traded to the New York Yankees for utility man Wilson Betemit and minor league pitchers Jeffrey Marquez and Jhonny Núñez. Swisher was acquired to be the Yankees starting first baseman. However, the Yankees signed Mark Teixeira later in the offseason, who took the starting role. At the end of spring training, manager Joe Girardi announced that Xavier Nady would be starting in right field while Swisher would be a bench player. Due to the perceived logjam, many teams reportedly pursued Swisher, but the Yankees opted to keep him as a reserve outfielder and first baseman.

On April 9, 2009, in a game against the Baltimore Orioles, Swisher started for the first time as a Yankee in right field, replacing Xavier Nady who was playing DH to give Hideki Matsui a rest. Swisher went 3-for-5 with a home run and tying his career high of five RBIs. Just five days later, Swisher became the starting right fielder after Nady went on the disabled list due to an elbow injury.

On April 13, 2009, in a game against the Tampa Bay Rays, Swisher pitched one inning in relief, allowing one hit and one walk before retiring the next three batters in a row, including a strikeout against Gabe Kapler in his first pitching appearance in the major leagues. He was the first Yankee position player to pitch since Wade Boggs in 1997 and the first Yankee to homer and pitch in the same game since Lindy McDaniel did it in Detroit on September 28, 1972.

Swisher hit his first postseason home run in the 2009 World Series. He got his only championship title as the Yankees eventually won the World Series against the Philadelphia Phillies in 6 games.

Due to a .128 batting average in the 2009 postseason, Swisher worked with hitting coach Kevin Long to reinvent his swing for the 2010 season. Swisher was a contestant in the 2010 All-Star Final Vote from July 4 to 8. Swisher lobbied for the post with a promotion commercial of him with a surf board to indicate that he would be surfing in Southern California since the game was to be hosted by the Los Angeles Angels of Anaheim. In what was to that date the closest vote in Final Vote history, he won the final place on the AL roster ahead of Red Sox first baseman Kevin Youkilis. Additionally, Swisher participated in the Home Run Derby. Swisher finished the season with a career-high .288 batting average and 29 home runs. Although Swisher was usually hitting in the bottom third of the lineup, he was moved into the #2 slot in the lineup after Nick Johnson went down with an injury and served as a buffer for the middle of the Yankees lineup.

In August 2009, People reported that Swisher was dating actress JoAnna Garcia. Swisher and García became engaged in May 2010, and married on December 11, 2010, at the Breakers Hotel & Resort in Palm Beach, Florida. The couple have two daughters, born May 2013 and June 2016.

In 2011, Swisher was moved down in the lineup to allow Curtis Granderson to hit second behind Derek Jeter and spent the majority of the season hitting sixth behind Robinson Canó. His fielding percentage ranked 2nd among all American League Right Fielders with a .996 behind Baltimore’s Nick Markakis. Although Swisher’s totals dipped a bit from his 2010 career year, he still managed to hit .260 and was one of four Yankees with at least 20 home runs (after Granderson, Teixeira, and Cano) and finished fourth on the team with 85 RBIs.

In 2011, Swisher guest starred as himself on two episodes of his wife’s sitcom, Better with You. The first episode aired February 16 and the second aired February 23. He also appeared in the episode “Perfect Week” of How I Met Your Mother, which aired in February 2010.

Swisher released a children’s music album titled “Believe” on August 9, 2011. A percentage of the proceeds was to be donated to “Swish’s Wishes”, a charity started by Swisher for children who are facing health crises. The 12-song album features guest appearances from Bernie Williams and Barry Zito. All of the songs recorded on the album are cover songs that were selected by Swisher. The album peaked at #3 on the chart of iTunes Children’s Albums.

On November 9, 2012, Swisher declined a $13.3 million one-year qualifying offer from the Yankees, making him a free agent. Under the new collective bargaining agreement, the Yankees received a compensatory pick because the Indians signed Swisher but it was not the Indians’ pick. Cleveland, in turn, surrendered its highest pick outside of the top ten but that pick did not go to the Yankees, it was just skipped in the draft.

On December 23, 2012, Swisher agreed to a four-year, $56 million contract with the Cleveland Indians. The contract reportedly included a fifth year vesting option worth $14 million, making the total contract worth $70 million. The deal became official on January 3, 2013. He soon called a section of the stadium Brohio. The Yankees received a compensation draft pick for the 2013 MLB draft as a result of losing Swisher, subsequently using it on Aaron Judge.

The 2014 season marked a difficult one for Swisher, as injuries had caused him to post career lows in batting average (.208), games played (97) and home runs (8). On June 19, 2014, after going 0–4 at the plate with three strike outs, and with two outs and two strikes, Swisher hit a walk-off grand slam against the Los Angeles Angels of Anaheim propelling the Indians to a 5–3 win in ten innings. On August 20, the Indians announced that Swisher would have arthroscopic surgery on both of his knees, ending his season.

On August 7, 2015, the Indians traded Swisher and Michael Bourn with cash considerations to the Atlanta Braves for Chris Johnson. Swisher batted .195 in 46 games for the Braves. On March 28, 2016, the Braves released Swisher, despite owing him $15 million for the 2016 season.

On April 14, 2016, Swisher signed a minor league contract to return to the Yankees. They assigned him to the Scranton/Wilkes-Barre RailRiders of the Class AAA International League. Playing first base, Swisher batted .255 with seven home runs and 25 RBIs in 55 games. The Yankees opted not to promote Swisher to the major leagues, in spite of injuries suffered by Mark Teixeira, Dustin Ackley, and Chris Parmelee. On July 2, Swisher opted out of his contract to be with his family following the birth of his second daughter. He announced his retirement on February 17, 2017, and became an analyst for Fox.