On August 15, 2012, Hernández threw the 23rd perfect game in MLB history, defeating the Tampa Bay Rays at Safeco Field by a 1-0 score.

[6] One reason Hernández chose the Mariners is that his idol, fellow Venezuelan pitcher Freddy García, was pitching for the team at the time.

His agent, Wil Polidor, also attributed the decision to the influence of Hernández's father Félix Sr., a trucking business owner who handled negotiations for his son.

[citation needed] He started the 2004 season with the Inland Empire 66ers in the California League before being promoted to the Double-A San Antonio Missions, and finished a combined 14–4 with a 2.95 ERA and 172 strikeouts in 1491⁄3 innings pitched.

[10] 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.

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.

For his first full year in the major leagues, Hernández arrived in spring training out of shape and had his preparation for the season interrupted by shin splints.

He recovered in time to begin the season in the starting rotation, where he often struggled, but occasionally showed flashes of the potential that had generated such hype.

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).

[13] During the offseason, Hernández returned to his parents' home in a modest Valencia neighborhood, while awaiting completion of a house for himself, his girlfriend and daughter.

[14] A Seattle Times profile of his life in Venezuela, with its relaxed daily routine, raised eyebrows among those who remained concerned about his conditioning.

He then picked up a workout regimen, including an improved diet, daily running, and regular weight training, to lose about 20 pounds.

This put Hernández in much better physical condition upon his return to the United States in January, when he began a throwing program in advance of spring training.

Hernández thrust himself into the national spotlight with his next start on April 11 against the Boston Red Sox, a much-hyped duel with Japanese import Daisuke Matsuzaka, who was making his home debut at Fenway Park.

Hernández lived up to his end and upstaged the matchup of Matsuzaka pitching to his countryman, Ichiro Suzuki, by hurling no-hit ball for seven innings, finishing with a one-hit, complete-game shutout in a 3–0 victory.

After undergoing an MRI exam that night, he was examined the next day and was diagnosed with a strained flexor-pronator muscle in his forearm and was placed on the disabled list.

Two planned returns were put off as the team took a cautious approach in bringing him back, although it opted not to send him to the minor leagues for a rehabilitation assignment.

On June 23, in his only at bat of the season, Hernández hit his first major league home run, a grand slam, off Johan Santana of the New York Mets.

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.

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.

[29] The creation of the Mariners marketing director,[29] it marked the first time in Major League Baseball that a stadium promotion was designed around a popular player.

[34] 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.

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.

[35] The contract made him the highest-paid pitcher in Major League history until it was surpassed by the $180 million extension signed by Justin Verlander of the Detroit Tigers in March 2013.

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.

Hernández pitched the first inning of the All-Star game, he gave up one infield base hit and struck out two National League batters.

[50][51] After spending 2 months on the disabled list, he was activated on the weekend of June 24, winning a game against the Houston Astros 13-3 and striking out eight batters.

Hernández is also the Seattle Mariners Ambassador for the Pepsi Refresh Project, raising money for the Washington State Coalition Against Domestic Violence.

[82] Hernández was inducted into the Seattle Mariners Hall of Fame on August 12, 2023, and also made the first ceremonial pitch of Game 3 of the 2022 ALDS against the Houston Astros.