In school, Vela played both basketball and football simultaneously, which caused many problems between his coaches. His father made him decide to focus on only one sport at the age of 12, in which Vela chose football. Enrique Vela was frustrated at the fact that his son was not being scouted due to living in Cancún. Around the same time, José Luis Real of C.D. Guadalajara’s youth system sent scouts to Cancún in 2001, where Vela caught their eye. He was summoned to a youth tournament in Buenos Aires with Guadalajara as a small trial period with unpaid expenses.

In 2003, during a local competition held in Ciudad Victoria, Vela was seen and was presented with offers with local teams of the Primera División. He eventually joined Guadalajara in 2003, though he never received a call up to the club’s first-team squad, thus not being able to make his professional debut in Mexico.

Vela attracted interest from a number of European clubs, and eventually Arsenal won the race for his signature in November 2005 on a five-year deal for a £125,000 fee that rose to £550,000 after he played 50 first-team games. However, since English work permit restrictions for non-EU citizens prevented him from playing in England, Arsenal quickly loaned him out to Spanish club Celta de Vigo in February 2006, but he was returned right away with no games played.

Vela played in the 2005 FIFA U-17 World Championship, held in Peru, where he helped Mexico to victory. He would go on to score 3 goals in the group stage, 1 against Uruguay in a 2–0 win and 2 against Australia in a 3–0 win. He would also score Mexico’s final goal in a 3–1 victory against Costa Rica during a.e.t. during the quarterfinals, and once reaching the final against Brazil, he scored Mexico’s first goal in their 3–0 victory. He subsequently finished as top scorer with five goals, claiming the Adidas Golden Boot.

After his loan spell with Salamanca ended, bigger clubs of La Liga, such as Levante, Osasuna, and Almería, were all interested in taking him on loan from Arsenal for whom he was still ineligible to play as he still had yet to receive a work permit. Eventually, a one-year loan move to Osasuna was agreed, with the option of an extension for another year. No permanent option, however, had been included in the deal. On 31 October 2007, he scored his first goal with Osasuna, in a match against Real Betis, a performance that went on to earn several plaudits from the Spanish press.

During his stay at Osasuna, Vela made his international debut for the senior national team on 12 September 2007, in a friendly match against Brazil, losing 3–1. On 18 October 2007, he scored his first senior international goal for Mexico in a friendly against Guatemala in Los Angeles.

On 22 May 2008, Vela was granted a work permit that allowed him to play in England. Arsenal manager Arsène Wenger confirmed that Vela would be involved with the first team in the coming season and that he viewed Vela as a striker in Eduardo’s mould.

Vela made his competitive debut for Arsenal on 30 August 2008 in their Premier League match against Newcastle United, coming on as a substitute for Robin van Persie in the 63rd minute. Arsenal won the match 3–0. In his full debut on 23 September 2008, against Sheffield United in the League Cup, Vela scored a hat-trick in a 6–0 win, with his second goal voted as one of Arsenal’s Greatest 50 Goals. The match was also notable for featuring Arsenal’s youngest ever side, with an average age of 19.

On 8 June 2008, Vela scored his second senior international goal in a friendly against Peru in the 20th minute to help Mexico to a 4–0 victory. A match later for Mexico, he scored in their 2010 FIFA World Cup qualifying opener against Belize making the match 1–0. In the return leg against Belize, he again scored the opening goal of the match and beginning the 7–0 rout in favour of El Tri.

On 8 March 2009, in the FA Cup Fifth Round tie against Burnley, Vela scored the first goal in a 3–0 win by chipping the ball over the keeper and into the goal. He scored his first goal in the Premier League for Arsenal away to Portsmouth on 2 May 2009 making him just the second Mexican player to score a goal in the Premier League. On 28 April, Vela was excluded from Arsenal’s training session as a precaution due to the 2009 swine flu outbreak. Two of Vela’s friends from Mexico visited him over the weekend and Arsenal were asked to keep him away. He returned to training the next day, however, after being given the all-clear.

Vela missed Arsenal’s pre-season campaign of the 2009–10 season after suffering an ankle injury which kept him out until September. He returned to action on 22 September by coming off the bench in Arsenal’s 2–0 win by assisting the first and scoring the second goal against West Bromwich Albion in the League Cup. On 21 November 2009, he made his first appearance of the season in the Premier League away to Sunderland, playing 21 minutes after coming on as a substitute for Eduardo. Vela renewed his contract with Arsenal on 10 December 2009. On 4 May 2010, Vela played his 50th game in an Arsenal shirt, against Blackburn Rovers. On 9 May, he scored the fourth goal of Arsenal’s victory over Fulham.

In July 2009, Vela represented Mexico at the 2009 CONCACAF Gold Cup. He started in Mexico’s opener against Nicaragua. Five minutes into the match, an opposing player tackled Vela and he fell awkwardly on his right leg. X-rays, however, showed he did not break anything and could play again in the tournament. Mexico advanced to the semi-finals against Costa Rica, where Vela would make his return in the 81st minute. After extra time, the game was tied 1–1 and went to penalties. After Guillermo Ochoa saved Froylán Ledezma’s penalty, Vela scored Mexico’s fifth penalty to send them to the final. In the final against the United States, Vela was brought on at half time with the score deadlocked at 0–0. Mexico went on to defeat the United States 5–0 with Vela providing the pass to Giovani dos Santos for the first penalty, creating the second goal, scoring the third and assisting the fourth.

On 10 October 2009, during a World Cup qualifying match against El Salvador, Vela scored one goal and provided an assist in a 4–1 victory, helping Mexico for the tournament.

Vela scored his first goal of the season against Bolton Wanderers in a 4–1 home win on 11 September 2010. On 15 September, Vela scored two goals in the UEFA Champions League when Arsenal beat Portuguese side Braga 6–0.

On 3 June 2010, Vela scored his first international goal against a team from Europe, in a friendly match against Italy. He scored the first goal of the game with an assist from Giovani dos Santos. Mexico would win the match 2–1. In the opening match of the tournament against hosts South Africa, he was a starting left-winger, coming out on the 69th minute for Cuauhtémoc Blanco in a 1–1 tie. In the following group match against France, Vela was subbed off in the 31st minute for Pablo Barrera due to injury and would miss the following matches against Uruguay and Argentina.

On 21 September 2010, the Mexican Football Federation announced that Vela and teammate Efraín Juárez would be suspended from the Mexico national team for six months for their involvement in a party on 7 September in Monterrey following a game with Colombia. Vela and 12 other players were also fined 50,000 Mexican pesos (approximately US$3,953 as of 24 September 2010), used to help the flood victims in the Mexican state of Veracruz.

On 28 January 2011, Vela joined West Brom on loan until the end of the 2010–11 season. He made his debut on 1 February 2011 in a 2–2 draw against Wigan Athletic, playing 58 minutes of the game. He scored his first goal coming in as a substitute for the Baggies in his third match for the club with a 92nd-minute equaliser against Wolverhampton Wanderers on 20 February 2011. Vela once again scored for West Brom in the dying minutes of a game against Stoke City to salvage a 1–1 draw after coming on as a late substitute.

On 15 August 2011, Arsenal announced that Vela would be loaned out to Spanish club Real Sociedad, subject to a medical. After passing the medical exams, he was officially presented on 17 August 2011. On 4 December 2011, Vela scored a bicycle kick goal to equalise for Real Sociedad, his second of the season, against Málaga before teammate Diego Ifrán scored a late winner to make the score 3–2. Vela scored the only goal for Real Sociedad in a 2–1 loss to Barcelona, making it his third goal for the season.

After his suspension, Vela returned to the national team after head coach José Manuel de la Torre called him up for a friendly match against Venezuela in March 2011, his final match with the national team for three years. He was omitted from that year’s Gold Cup which Mexico went on to win. Vela was included in the preliminary roster for the 2011 Copa América but Arsenal refused to allow him to go, citing that it wasn’t a CONCACAF tournament. He refused a call-up to participate in the 2012 London Olympics, which Mexico went on to win, due to wanting to establish himself with his new club Real Sociedad. He declined a third time to join the national team in March 2013 for the 2014 World Cup qualifiers against the United States and Honduras due to personal reasons.

After making over 30 appearances in all competitions and scoring 12 goals, Vela was officially transferred to Real Sociedad from Arsenal on 17 July 2012, for an undisclosed fee. The deal was confirmed by Arsenal on 10 August. He was given the number 11 shirt. During the 2012–13 season, Vela played predominantly on the right wing and scored 14 goals, as well as having nine assists. There had been speculation in the media that he would return to Arsenal, however no talks took place between the two teams.

After De La Torre was sacked, Vela declared his wish to return to play for Mexico. In September 2013, Víctor Manuel Vucetich called him up for World Cup qualifiers against Panama and Costa Rica; however, Vela declined once again to come back to the national team. Afterwards, Vucetich refused to make any more comments regarding Vela, calling it a “closed case”. On 3 February 2014, new national team coach Miguel Herrera flew to Spain with officials from the Mexican Football Federation to meet with Vela and gauge his interest in representing the national team. After the meeting, Vela expressed that he was not “100 percent mentally ready to represent Mexico”, subsequently ruling out his participation in the 2014 FIFA World Cup.

On 20 January 2014, it was announced that Vela had won La Liga Player of the Month for December after his performances against clubs such as Real Betis, Granada, Real Madrid, and Barcelona.

On 5 May 2014, Vela scored in the 1–1 draw against Granada. The goal was Vela’s 15th league strike of the season—surpassing his tally of 14 from the previous season—and his 20th in all competitions. He was nominated at the season’s LFP Awards for the Best Forward in the league, losing out to Cristiano Ronaldo. On 24 June, Vela signed a four-year contract extension which will keep him at Real Sociedad until 2018.

Vela scored his first goal of the 2014–15 season in Real Sociedad’s 4–2 win against Real Madrid on 1 September 2014. On 28 November, he scored all of the side’s goals as they beat Elche 3–0 for new manager David Moyes’ first victory at the club. These were three of his four league goals that month, which once again earned him the La Liga’s Player of the Month award.

In November 2014, after a three-year absence, Vela accepted a call up to the national team for the friendly matches against the Netherlands and Belarus. He scored twice on his return as Mexico defeated the Dutch 3–2 at the Amsterdam Arena on 12 November.

On 31 January 2015, during Real Sociedad’s 1–4 league defeat to Real Madrid, Vela was subbed off in the 17th minute due to a knee injury, which was later reported to be ligament damage, and would require surgery. Though it was initially reported that Vela would miss the remainder of the season, it was confirmed through a club statement that the injury was an internal meniscus tear and that Vela would be out for two months. He made his return on 22 March against Córdoba, being substituted on for Esteban Granero in the 66th minute and providing an assist in Real Sociedad’s 3–1 win.

On 25 October 2015, Vela scored his first two goals of the 2015–16 season in Real Sociedad’s 4–0 win over Levante.

Vela was called up by Miguel Herrera to participate in the 2015 CONCACAF Gold Cup, scoring in the team’s opening match against Cuba on 9 July. On 15 July, Vela scored his second goal in the competition in Mexico’s 4–4 draw against Trinidad and Tobago. In the quarterfinal and semi-final matches against Costa Rica and Panama, respectively, Vela received two yellow cards, meaning he would miss the final against Jamaica, during which Mexico won the tournament.

On 9 March 2016, it was reported that Vela had been separated from the first team after he failed to report for training two days earlier, claiming he was suffering from gastroenteritis, though a photo began circulating on social media of him attending a Chris Brown concert in Madrid hours after the team’s 1–1 draw against Levante. He was ultimately fined by the club and ruled out for the team’s next match against Celta de Vigo. Sociedad manager Eusebio Sacristán, however, named Vela in the squad for the match against Celta, appearing as a second-half substitute in the 0–1 loss.

Vela became a father in November 2016 to a son Romeo, with his Spanish girlfriend Saioa Cañibano, whom he met during his time at Real Sociedad.

On 10 April 2017, Vela played in his 200th league match for Real Sociedad in the side’s 3–1 victory against Sporting de Gijón, as well as becoming the foreign player with the second-most appearances for the club behind Darko Kovačević.

On 8 August 2017, Real Sociedad announced an agreement with Major League Soccer for Vela to move to the league in 2018. Two days later, it was announced that he would join expansion team Los Angeles FC as their first Designated Player when the transfer window opens on 1 January 2018.

On 20 December 2017, Vela played in his final match for Real Sociedad, scoring the final goal in the team’s 3–1 win over Sevilla.

On 8 August 2017, it was announced that Vela had been signed by Los Angeles FC, becoming the first designated player of the team and officially joining the team on 1 January 2018.

In May 2017, he was called up by Juan Carlos Osorio to be included in the roster to participate in the 2017 FIFA Confederations Cup in Russia. Appearing as a starter in Mexico’s first group stage match against Portugal, he would provide a low cross assist for Javier Hernández to score Mexico’s first goal in a match that was eventually tied 2–2. He would go on to appear in Mexico’s final group stage match against Russia and third place play-off against Portugal.

On 4 March 2018, Vela made his debut with Los Angeles FC, providing an assist for Diego Rossi’s goal in the team’s 1–0 victory over Seattle Sounders FC. On 10 March, Vela would score his first goal with Los Angeles, scoring the final goal in a 5–1 thrashing against Real Salt Lake. On 31 March, Vela became the first player ever to score in the El Tráfico derby against LA Galaxy; he scored the first two goals of the game in Los Angeles’ dramatic 3–4 defeat. On 13 April, he would score the first goal in a 2–0 win over the Vancouver Whitecaps. A week later he would go on to convert a penalty during Los Angeles’ 5–3 win over Montreal Impact. On 13 May, he would score Los Angeles’ second goal in a 2–2 tie against New York City FC. A couple of days later he would score his teams’ only goal against the Portland Timbers in a 2–1 loss.

On 26 July 2018, after conducting a popular vote on Twitter, Vela was voted to captain the MLS side in the 2018 MLS All-Star Game against Juventus, where they initially tied the match 1–1 but went on to lose 5–3 in penalties. Following the departure of club captain Laurent Ciman, Vela was named as succeeding captain. On 22 September 2018, Vela provided two assists to Walker Zimmerman in the 2–0 victory over San Jose Earthquakes. On 12 October, in a league match against Houston Dynamo, he was involved in all of his team’s goals in a 4–2 victory as he scored a brace and contributed two assists. In November 2018, he would be named into the MLS Best XI of 2018.

In May 2018, Vela was named in Mexico’s preliminary 28-man squad for the World Cup, and in June, he was named in the final 23-man squad. On 23 June, in Mexico’s second group stage match against South Korea, he scored their first goal via a penalty kick in the 2–1 victory; it was also his first World Cup goal for Mexico. He appeared in all group stage matches and the round of 16 loss against Brazil. Following the departure of manager Osorio, Ricardo Ferretti was appointed as interim manager of the national team and did not include him in the roster for the post-World Cup September friendlies. Vela insisted on respecting Ferretti’s decision and wished them luck.

On 30 March 2019, Vela scored his first hat-trick with LAFC in their 5–0 away win against San Jose Earthquakes. Vela scored both goals in a 2–3 loss to city rivals LA Galaxy on 19 July; his first goal was his 20th league goal of the season and he became the fastest player in MLS history to reach that milestone.

In January 2019, Gerardo Martino was named as the new manager for the national team and did not call up Vela for his first friendlies in March, stating he wanted to see other players in action and that the door is not necessarily closed on future call-ups, although it was unclear if Vela wanted to continue his international career. In May, it was reported that Vela was not interested in being called up for the 2019 CONCACAF Gold Cup. In November, he stated that he is willing to return to the national team if called up. In May 2020, he declared that the 2018 World Cup was his final appearance with the national team.

On 4 March 2020, Los Angeles FC announced that Vela had obtained a green card, qualifying him as a domestic player for Major League Soccer roster purposes.