On 8 April 2010, Hernández agreed a deal to sign for Manchester United for an undisclosed fee, subject to a work permit application. The previous day, Hernández had been present at Manchester United's Champions League quarter-final win over Bayern Munich at Old Trafford. The deal was conducted in complete secrecy; Hernández's agent was kept in the dark, as was his grandfather Tomás Balcázar, who thought Hernández was going on a trip to Atlanta in the United States. As part of the deal, United played a friendly against Chivas to open the Mexican club's new stadium on 30 July. On 27 May, the work permit was granted, allowing the transfer to be made official on 1 July.
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. Two days later, Hernández scored against Manchester United while playing in a friendly for his old club, Chivas, scoring the inaugural goal at the recently constructed Estadio Omnilife; he started the game in a Chivas jersey and scored after just eight minutes. He switched sides at half-time, but he was unable to prevent a 3–2 defeat for Manchester United. He scored for the third pre-season game in a row as he netted in a 7–1 victory over a League of Ireland XI at the newly built Aviva Stadium on 4 August.
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. He came on at the start of the second half and got on the end of a pass from Antonio Valencia before the Mexican's shot deflected off his own face and into the net. On 16 August, Hernández made his Premier League debut as he replaced Wayne Rooney in the 63rd minute of their 3–0 home victory over Newcastle United. He scored his first Champions League goal on 29 September, coming off the bench to score the only goal in an away win over Valencia. He scored his first league goal for United in a 2–2 home draw against West Bromwich Albion on 16 October. Eight days later he scored his first brace for the club, also his first away league goals, in a 2–1 away win over Stoke City. 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. On 1 January 2011, he came off the bench to head the winning goal in a 2–1 away win over West Bromwich Albion. Hernández became the top scoring Mexican in Premier League history after opening the scoring in a 2–1 home victory over Stoke City on 4 January.
Hernández scored another goal in his first match for Mexico since the World Cup, in a friendly against world champions Spain on 11 August 2010. He scored after just 12 minutes of the match, but David Silva equalised for Spain in the last minute of play to claim a 1–1 draw. Hernández scored his and Mexico's first international goal of 2011 as he opened the scoring in a 2–0 win over Bosnia and Herzegovina on 9 February. On 26 March, Hernández scored two goals in an international friendly against Paraguay. He first connected with a pass from Pablo Barrera in the sixth minute of the match, before scoring off a low cross in the 29th minute, three minutes after teammate Andrés Guardado had made the score 2–0. He exited to a standing ovation in the 65th minute.
Hernández is the son of Javier Hernández Gutiérrez, who played for three clubs in Mexico and was a member of the Mexico squad at the 1986 FIFA World Cup. Hernández Gutiérrez quit his job as manager of Guadalajara's reserve side in order to watch Hernández play in the 2010 World Cup in South Africa. Hernández is also the grandson of Tomás Balcázar, who also played for Guadalajara and played for the national side in the 1954 FIFA World Cup.