On 18 October, Villa was nominated for the Ballon d'Or, while nearly two weeks later, on 30 October, he was nominated for the FIFA World Player of the Year. After going three league games without scoring, Villa contributed two goals towards Valencia's 4–1 victory against Villarreal on 17 January 2010, the first of his two goals became his 100th league goal with Valencia. Another brace came against Getafe on 22 February 2010, the second goal being "a superb chip" (as described by ESPN) over Jordi Codina. On 18 March, Valencia went to the Weserstadion to play Werder Bremen in the Europa League. Villa scored a hat-trick, his third goal being of note, which was fired in from eight yards out. The match ended 4–4 while Valencia proceeded to the next round on away goals. On 4 May 2010, Valencia played Xerez; Villa did not start but came on as a substitute 62 minutes into the match, which ended 3–1. Valencia still had two more games to play in the league, although Villa did not feature, making the game against Xerez the last time he played for Valencia.
On 19 May 2010, Barcelona reached an agreement with Valencia for the acquisition of Villa for a €40 million transfer fee. Villa signed a four-year contract with Barça with the option for a fifth, worth a reported €7 million per season, thus following in the footsteps of his heroes Luis Enrique and Quini, both of whom, like Villa, started out at Sporting Gijón and ended up at Barcelona. On 21 May 2010, over 35,000 Barcelona supporters packed into Camp Nou to see Villa's presentation, where he revealed the kit Barcelona would use during the 2010–11 season. He was given his favourite number 7, a number which had been free at the club since Eiður Guðjohnsen left in 2009. He made his first appearance for the club in the second leg of the Supercopa de España, during the second half as a substitute for fellow Spanish international Pedro. His debut appearance would also see him win his first piece of silver-ware with the Catalonian side, as Barcelona won 4–0 and 5–3 on aggregate due to a hat-trick by teammate Lionel Messi. His first goal came during the Joan Gamper Trophy (an annual friendly competition) against Milan; Barcelona won 3–1 on penalties after the match had ended 1–1 during normal time.
On 29 August 2010, Villa made his La Liga debut with Barcelona against Racing de Santander, where he scored the third goal of the match to help seal a 3–0 victory. On 14 September 2010, he scored on his Champions League debut with Barcelona in a 5–1 victory over Panathinaikos.
Against Sevilla, on 31 October 2010, Barcelona won 5–0 against the Andalusian side, while Villa netted a brace. Villa's first El Clásico against Real Madrid came on 29 November 2010, where he scored two goals as Barcelona won 5–0 at the Camp Nou. Talking about the match, he commented that, "It's been a very important win. We looked for the victory and we got it. And the result and the manner in which we achieved it, you cannot ask for more." He then scored a goal against Real Sociedad, a match Barcelona won 5–0. He followed with a brace against Espanyol, helping Barcelona to a 5–1 win.
On 27 December 2010, Villa was named "Male Athlete of the Year" by the United States Sports Academy, as he edged fellow Spaniard Rafael Nadal and previous winner Manny Pacquiao for the title.
In 2010, Villa came first in the IFFHS "2010's World Top Goalscorer at International Level" rankings, he was subsequently selected as a part of Vicente del Bosque's 23-man squad for the 2010 FIFA World Cup. In a friendly against Saudi Arabia on 29 May 2010, Villa scored the first of Spain's goals as they won 3–2 at the Tivoli Neu – the stadium where he scored his hat-trick against Russia during Euro 2008. Failing to score in Spain's next match against South Korea, he opened the score sheet in Spain's next match against Poland, in which Spain won 6–0, recording Poland's their worst defeat in 50 years.
Spain's first match of UEFA Euro 2012 qualifying was against Liechtenstein on 3 September 2010, Villa scored the second goal of the match which eventually ended 4–0. It was believed that this goal meant that he had equalled Raúl's record 44-goal tally, however after many debates about whether he or Dariusz Dudka scored the first goal in Spain's 6–0 win over Poland, FIFA eventually decided that it was indeed an own goal by Dudka, meaning Villa's goal tally would remain at 43. On 12 October 2010, he finally equalled Raúl's record, scoring a penalty against Scotland and helping Spain see off the Scots in a 3–2 victory at Hampden Park.
In February 2010, Bernd Schuster was asked if Raúl did not favour Villa moving to Real Madrid, to which he responded, "I have a cough," which caused many to believe that he was implying the rumour to be true. Villa firmly ridiculed that idea by saying, "It is impossible that a player with as much class on and off the pitch as Raúl would speak poorly of me. I have always had a good relationship with Raúl, even though we have hardly met on international duty." Speaking about Raúl's record with the Spanish national team as the nation's leading top scorer, Villa said, "I've got 25 goals but he's got 44 and is still playing. I'd be delighted to reach that tally as I'd help the national team achieve great victories and, in many years' time, I could see my name on a [scorers' list] that another young lad was trying to beat. That would be great." On 25 March 2011, two years after making that remark, Villa surpassed Raúl as Spain's all-time top scorer.
In 2010, Villa sang alongside Grammy Award-nominated Spanish singer Ana Torroja on the song "Insurrection" by El Último de la Fila. The recording was made for the beneficiary project Voces X1FIN to help raise money to build an art and education school in Mali. Villa commented that footballers "are an example for society and we have to be ready to get involved in these projects, where we can help people who need it".