After graduating from high school, Hernández finally agreed to his first professional contract. Mariners director of international operations Bob Engle signed Hernández as a nondrafted free agent on July 4, 2002. Hernández received a large signing bonus of $710,000, although he said the Mariners were not the highest bidder. Other teams trying to sign him included the New York Yankees and the Atlanta Braves, with both teams reportedly offering more money than Seattle.

The following year, Hernández came to the United States and began pitching in the Mariners’ minor league system. In 2003, Hernández tore through Class-A with a 7–2 mark in Everett and Wisconsin. Returning to his native Venezuela to pitch in the winter league there, he held his own at 17 years of age against competition that included established major league players.

Hernández was named the Mariners’ minor league pitcher of the year in 2004, a season that also saw him make an appearance in the Futures Game. He started with Inland Empire in the California League, before being promoted to Double-A San Antonio, and finished a combined 14–4 with a 2.95 ERA and 172 strikeouts in 149⁄3 innings pitched.

At the beginning of 2005, Baseball America listed him as the No. 1 pitching prospect in baseball and No. 2 overall behind Joe Mauer. Hernández continued his success in 2005 with the Triple-A Tacoma Rainiers in the Pacific Coast League, posting a 9–4 record with a league-leading 2.25 ERA and 100 strikeouts in just 88 innings. He was selected for the Triple-A All-Star Game but did not participate as he spent a month on the disabled list with shoulder bursitis. He was also named the PCL Rookie of the Year and PCL Pitcher of the Year.

Soon after returning from his injury, Hernández was called up to the major leagues by the Mariners. He made his debut on August 4, 2005, in a 3–1 loss in a road game against the Detroit Tigers. At 19 years, 118 days, he was the youngest pitcher to appear in the major leagues since José Rijo in 1984. Hernández earned his first major league win in his next outing on August 9, 2005, pitching eight shutout innings in a 1–0 victory at home over the Minnesota Twins. Over his first several starts, he registered a streak of 112 batters faced before he allowed his first extra-base hit, a double by Jermaine Dye of the Chicago White Sox.

In 12 starts, Hernández posted a 4–4 record with 77 strikeouts and a 2.67 ERA. With 84 ⁄3 innings pitched, he exhausted his rookie eligibility. After the season, he became the focus of a disagreement over the possibility of his pitching in the 2006 World Baseball Classic. Although Hernández was placed on a provisional roster by his native Venezuela, the Mariners objected, citing his earlier injury and expressing concern about the stress on his arm from adding this competition to the demands of a full season in the major leagues at such a young age. Their appeal to the WBC technical committee was eventually upheld.

When he arrived in the major leagues, Hernández was given uniform number 59. In 2006, he switched to number 34, the same number Freddy García (since traded to the Chicago White Sox) had worn as a Mariner.

Concerned about avoiding possible injury to their young pitcher, the Mariners declared that they would limit the number of innings Hernández pitched to 200 (counting both the regular season and spring training). This required them to skip his turn in the rotation a couple times as the season went on, after the Mariners fell out of contention. To allow him to make one last start at the end of the year, the team decided to raise the limit to 205. His 191 regular-season innings were still the most on the team, and he finished 12–14 with a 4.52 ERA. His 12 victories and 176 strikeouts also led the Mariner pitching staff. He also threw the fastest fastball of all major league starters in 2006, averaging 95.2 miles per hour.

Based on his improved condition and a successful spring training, the Mariners indicated that in 2007 they would no longer limit the number of innings Hernández could pitch, focusing instead on pitch counts to avoid overuse. Hernández won the honor of being named the team’s Opening Day starter. He became the youngest pitcher chosen for this assignment since Dwight Gooden in 1985. He pitched eight innings of a 4–0 victory over the Oakland A’s, allowing three hits and two walks while setting a career high with 12 strikeouts.

Upon his return, Hernández initially battled to regain the form he had flashed in those first two starts of the year. Hernández finished the season with a 14–7 record. His victory over the New York Yankees on September 3, in his first appearance at Yankee Stadium, stopped a nine-game Mariner losing streak, but was not enough to keep the team from falling out of playoff contention. His 3.92 ERA for the season was the best among the team’s starters, and he again led the Mariners in strikeouts with 165. He again threw the fastest fastball of all major league starters in 2007, averaging 95.6 miles per hour.

Hernández finished the season with a 9–11 record posting 3.45 ERA and 175 strikeouts. He also threw the fastest fastball of all AL starters in 2008, averaging 94.6 miles per hour.

On June 19 against San Diego, Hernández threw a complete game, two-hit shutout against the Padres. This was his first complete game of the season and one of his best starts of his career. His sizzling performance in June (3–0 record, 0.93 ERA, 35 strikeouts) would earn him the AL Pitcher of the Month award for June, and on July 5, 2009, Hernández was selected along with outfielder Ichiro Suzuki as the Mariners representatives in the 2009 MLB All Star Game. He made the first All-Star appearance of his career in the sixth inning, tossing a hitless inning.

During the 2009 season, Hernández set career highs in wins, strikeouts, innings pitched, and earned run average. Hernández finished the season 19–5 with a 2.49 ERA and 217 strikeouts and was in strong contention for the AL Cy Young Award. Hernández ended up finishing second in the award voting behind Zack Greinke.

Hernández represented his native Venezuela in the 2009 World Baseball Classic. In his first outing, he pitched four innings in relief, surrendering only one hit while not allowing a run. In his next game, Hernández shut out Puerto Rico over 4 ⁄3 innings. Hernandez participated in the 2017 World Baseball Classic, playing for Venezuela.

On January 21, 2010, the Seattle Mariners and Hernández agreed to a 5-year contract extension worth about $78 million, which added to the involved offseason in which the Mariners traded for Cliff Lee and Milton Bradley. On June 3, 2010, Hernández struck out four batters in one inning. He did so by striking out Joe Mauer on a wild pitch before striking out Justin Morneau. He was the third Mariner to accomplish this feat.

On August 25, 2010, Hernández struck out David Ortiz to record his 1,000th career strikeout. He became the 3rd youngest pitcher to do so since 1952, behind Bert Blyleven and Dwight Gooden, and also the 4th overall, behind Bob Feller.

Hernández faced the Rangers on September 17, 2010 and was working on a no-hitter until Nelson Cruz broke it up with a home run in the eighth inning. In his next start, he threw a complete game two-hitter in Toronto, surrendering only one run on José Bautista’s 50th home run of the year in the first inning. The Mariners offense, however, was shut out by Blue Jays pitching and Hernández was dealt his twelfth loss of the season. Ten of Hernández’s twelve losses were in games where the Mariners were shut out or scored only one run, and four other times, the bullpen blew a lead Hernandez turned over to them.

In 2011 Hernández was selected to the American League All Star Team for the second time. He represented the Mariners alongside rookie starter Michael Pineda and closer Brandon League.

On August 31, 2011, Hernández struck out nine batters, giving him 204 strikeouts to that point in the season. It marked the third straight season in which he reached 200+ strikeouts. The only other pitchers to have three 200-K seasons at 25 or younger over the last 20 years are Clayton Kershaw, Kerry Wood and Yovani Gallardo. Kershaw did it in 2010, 2011, 2012 and 2013. Wood did it in 1998, 2001 and 2002. Gallardo did it in 2009, 2010, and 2011.

On May 28, 2011, a special cheering section for Hernández, dubbed “King’s Court”, debuted in Safeco Field on the foul territory side of the left field foul pole. The creation of the Mariners marketing director, it marked the first time in Major League Baseball that a stadium promotion was designed around a popular player. By popular demand, the cheering section was expanded from two to three sections – Sections 148, 149, and 150 – by the end of the year. Seats are sold at a discount and the ticket price includes a yellow “King Félix” T-shirt and a yellow placard imprinted with a large “K” to wave when cheering for strikeouts by Hernández. “King’s Court” is typically occupied by about 1,500 fans on days that Hernández starts. Hernández reportedly likes the cheering squad, but is able to maintain his concentration and not give in to the temptation to throw a fastball on an 0–2 count in response to his cheering fans. If there is a marquee matchup (duel of team aces), or a big/important game in which Hernandez pitches, there is another King’s Court added in the upper deck directly above the King’s Court. These sections are called the “High Court”.

On February 13, 2013, Hernández signed a seven-year extension with the Mariners worth $175 million, voiding the final two years of his previous deal and including a team option for 2020. The contract made him the highest paid pitcher in Major League history, until he was surpassed by the $180 million extension signed by Justin Verlander of the Detroit Tigers in March 2013. On April 22 in a 7–1 win against the Houston Astros, Hernández recorded his 100th career win. In that game Hernández pitched six innings allowed five hits, walked one and struck out nine. On July 6, 2013, Hernández was selected to his fourth All-star game. He pitched in the fourth inning, and let up one hit, but no runs were scored. Hernández had a bad August, going 1–4 with a 5.82 ERA and a .281 OBA. He made only 3 starts in September while trying to rest his oblique. In 31 starts in 2013, Hernández went 12–10 with a 3.04 ERA and 22 quality starts, striking out 216 in 204 ⁄3 innings. He was 5th in the American League in strikeouts, and 6th in ERA.

On October 19, 2013, Carlos Peguero’s wife Maria was charged with three counts of wire fraud after allegedly making $180,000 in online purchases with the debit card belonging to Hernandez’s wife. Carlos Peguero told investigators he was unaware of any fraudulent purchases, believing his wife’s brother worked for Saks Fifth Avenue, with whom the fraudulent purchases were made. Carlos is not a target of the investigation.

On May 12, Hernández was ejected for the first time in his career against the Tampa Bay Rays at Safeco. When he left the game in the seventh after a three-run double, Hernández started shouting at the home plate umpire in disagreement with his calls. On June 8, Hernández struck out a career high 15 batters against the Rays in a 5–0 win. Hernández got a no-decision, as all five runs were scored after he left the game. Hernández got his tenth win on June 29, 2014 against the Cleveland Indians in a 3–0 victory in eight shutout innings with just one hit. Fernando Rodney got his 23rd save pitching a perfect ninth to secure the victory.

Hernández won his second American League ERA title with a 2.14 ERA, three points under that of Chicago White Sox pitcher Chris Sale. He achieved the ERA title on the last day of the season, on September 28 against the Angels going 5.1 innings allowing no runs and seven strikeouts. In 2014, Hernández set the lowest ERA mark by an AL pitcher since Pedro Martínez in 2000. He also set the lowest WHIP by an AL pitcher (0.92) since Martinez in 2000. He finished second in the AL Cy Young Award race behind Cleveland Indians pitcher Corey Kluber. These two faced each other on July 30. Hernández lost 2–0 against him.

On August 15, Hernández threw the first perfect game in Mariners history and the 23rd and most recent perfect game in MLB history. He recorded 12 strikeouts, five of which were in the last two innings, against the Tampa Bay Rays in a 1–0 victory. It was the fourth no-hitter in team history and Hernández joined Randy Johnson and Chris Bosio as the only Mariners pitchers to throw individual no-hitters. One of their no-hitters were combined, needing six pitchers to do so on June 8 against the Dodgers. His perfect game was the last no-hitter thrown in the American League for the next three years, until his Japanese teammate, Hisashi Iwakuma succeeded him on August 12, 2015.

Hernández has been known to throw a sinker (two-seam fastball), a slider (he avoided the slider early in his career because the team was concerned it might injure his arm), a changeup, and a curveball. His fastball no longer reaches the 100 mph as it did when he first broke into MLB, but he has become a much craftier and more efficient pitcher over the years. In 2016, Hernández’s sinker averaged about 90–92 mph; four-seam fastball at 90–92 mph; slider at 84–86 mph; curveball at 79–81 mph; changeup at 87-88 mph; and the occasional cut fastball at 88–90 mph. The changeup was his most commonly used two-strike pitch, and had the highest whiff rate of his pitches.

On March 29, 2018, Hernández made his tenth Opening Day start in a row. Only Jack Morris, Robin Roberts and Tom Seaver have made more consecutive Opening Day starts. He pitched 5.1 innings, giving up no earned runs on two hits, two walks, and four strikeouts. The Mariners won the game 2–1. On July 10, he was placed on the disabled list for the third straight season.

On August 7, 2018, Hernández allowed 11 runs in six innings, in a loss to the Texas Rangers. This raised his ERA to a career-worst 5.73 in 23 starts. After the game, manager Scott Servais would not commit to his next start in the rotation. On August 9, Servais removed Hernández from the starting lineup. On August 10, Hernández was removed from the starting rotation and transitioned to the bullpen. He made his first appearance as a reliever on August 14 against the A’s when starting pitcher James Paxton was struck by a line drive. Hernández temporarily returned to the rotation with Paxton on the disabled list. Hernández finished the worst season of his career, going 8–14 with an ERA of 5.55 in 155 ⁄3 innings.

In September 2018 Hernández became naturalized as a United States citizen.

On May 11 against the Boston Red Sox, Hernández recorded his 2,500th strikeout by striking out Michael Chavis, becoming the sixth-youngest pitcher in Major League history to reach the 2,500 strikeout mark. However, he was placed on the 10-day injured list after the start with a right shoulder strain. In June, he went on a rehabilitation assignment with the Triple-A Tacoma Rainiers. On September 26, 2019, Hernández pitched in what could be the final game of his Seattle Mariners career in a 3–1 loss to the Oakland Athletics. In the game, he threw for 5 ⁄3 innings, gave up 5 hits, 3 runs and walked 4 batters while striking out 3. Hernández ended the 2019 season with a 1–8 record, 57 strikeouts, and an ERA of 6.40 in 71 ⁄3 innings. On October 31, Hernández became a free agent.

On January 20, 2020, Hernández signed a minor league deal with the Atlanta Braves for $1 million. On July 4, 2020, Hernández announced he would be opting out of the 2020 season due to concerns related to the COVID-19 pandemic. He became a free agent on November 2, 2020.