[9] Whilst playing football professionally, Hernández was also taking business administration classes at Universidad del Valle de Atemajac.

On 25 February 2009, during a group stage match of that year's edition of the Copa Libertadores, Hernández came on as a substitute and scored a brace against Everton in a 6–2 home victory.

[26] Hernández made his United debut on 28 July, coming on as a 63rd-minute substitute for Nani in the 2010 MLS All-Star Game at the NRG Stadium, Houston; he scored his first goal for the club 18 minutes later, lobbing the ball over Nick Rimando from just outside the area after a long through-ball from Darren Fletcher.

[30] Hernández made his competitive debut on 8 August and scored his first goal in the process, netting United's second of a 3–1 victory over Chelsea in the 2010 FA Community Shield.

[35] Two days on from this display, he came off the bench to score a last-minute winner, his first ever League Cup goal, in a 3–2 win over Wolves which sent them through to the quarter-finals where they were then knocked out by West Ham United.

[51] Hernández capped his debut season with Manchester United by winning the Sir Matt Busby Player of the Year award on 18 May which was voted for by the fans.

[53] On 5 July 2011, the International Federation of Football History and Statistics named Hernández as the "World Goalgetter 2011", with 13 goals, ahead of other players such as Cristiano Ronaldo, Giuseppe Rossi, and Lionel Messi.

[54] After participating in the 2011 CONCACAF Gold Cup with Mexico, Hernández returned to Manchester United to begin pre-season training in New York ahead of the 2011 MLS All-Star Game.

On 26 July 2011, he was taken to the hospital after suffering a minor concussion after he was hit on the head with a ball during a training session; he was cleared the next day but did not take part in the game.

At the end of the match, Hernández claimed the hat-trick, but replays showed that his shot for United's second goal was hit wide until turned into his own net by Villa defender Ron Vlaar.

[91] In the tournament's semi-finals, his goal from Adnan Januzaj's cross in the last minute of extra time forced a penalty shootout, which United lost to Sunderland.

[92] On 29 August 2015, it was reported that Manchester United manager Louis van Gaal had told Hernández he could leave the club before the closure of the transfer window.

[103] On 31 August 2015, it was announced Hernández signed a three-year contract with Bundesliga club Bayer Leverkusen for an undisclosed fee,[104] reportedly £7.3 million.

[126] On 17 September, Hernández scored his first goal of the Bundesliga season at Eintracht Frankfurt, however he missed a chance to equalise late from the penalty spot in the 2–1 loss.

[127] The following week at FSV Mainz 05, Hernández collected a perfect hat-trick that included a stoppage time winner, the third hat trick of the Bundesliga season.

[136] On 24 July 2017, Hernández joined English club West Ham United for an undisclosed fee, reported to be around £16 million, signing a three-year contract.

[142] Following the sacking of Slaven Bilić and the appointment of David Moyes as manager, there were fears Hernández would be excluded at West Ham as he was at Manchester United.

[147] On 28 August 2018, Hernández scored West Ham's third goal in injury time of a 3–1 victory over AFC Wimbledon in the second round of the EFL Cup.

[156] On 30 August, Hernández handed in a transfer request to West Ham and flew to Spain to complete a medical ahead of a proposed €8 million move to Sevilla.

[183] During the club's June 7 quarterfinal match against Real Salt Lake in the 2023 U.S. Open Cup, Hernández suffered a torn ACL, ending his 2023 season.

[185] On 24 January 2024, Hernández returned to Mexico, as he signed a two-year contract, with an option for an additional year, with Guadalajara, the club where he began his professional career in 2006.

[195] On 11 June, Hernández made his FIFA World Cup debut during the opening game of the 2010 tournament against South Africa in a 1–1 draw, coming on in the 73rd minute to replace Guillermo Franco.

On 23 June, called up by Miguel Herrera, Hernández scored Mexico's third goal against Croatia in their 3–1 victory after coming on as a substitute at Arena Pernambuco to qualify the team for the round of 16.

[215] On 1 July 2015, Hernández sustained a broken collar bone during a friendly match against Honduras, ruling him out of the that year's CONCACAF Gold Cup,[216] which Mexico went on to win.

He was in the starting lineup in Mexico's first World Cup game against Germany at the Luzhniki Stadium in Moscow and made an assist to Hirving Lozano to go on to win the match 1–0.

[237][238] He has been described as one of the few players who seem capable of appearing behind a defender's back to knock in the ball from two yards, with his playing style being compared to that of German striker Miroslav Klose.

[239] Rudi Völler, sporting director of Bayer Leverkusen, has praised Hernández for his keen positioning in front of the goal, saying: "he certainly doesn't win every tackle, but he has an incredible sense of where the ball will end up".

[239] Former Manchester United manager Sir Alex Ferguson described Hernández as two-footed, very quick, in possession of a good spring, and a natural goalscorer.

[241] In a May 2016 interview with Sports Illustrated, Hernández commented on his abilities inside the penalty area, describing the intuition he has in knowing where an impending cross will fall from a teammate and outsmarting opposing defenders.

[255][256] In January 2019, Hernández and his then wife Sarah Kohan, an Australian model of Romanian descent[257] and travel blogger, announced on Instagram that they were expecting their first child.