During the 2005 FIFA U-17 World Championship, which his team won, Dos Santos assisted half of the goals of Mexico during the tournament, a feat that won him the Adidas Silver Ball as the second best player of the tournament, finishing behind only to Brazilian midfielder Anderson.

In 2006, Dos Santos was invited on the pre-season tour of Barcelona’s senior squad; during a friendly match on 29 July 2006, he scored in his senior team debut game against Danish club AGF Aarhus. On 28 November 2006, Barcelona included Dos Santos in their 23-man squad for the FIFA Club World Cup in Japan.

During mid-2007, Dos Santos was once again invited to join Barcelona’s senior squad on their pre-season tour. On 29 August 2007, he received dual nationality and was included in the official first team squad. He made his competitive and league debut on 2 September 2007 (at 18 years and 114 days) during a 3–1 home win against Athletic Bilbao, coming on for Thierry Henry in the 62nd minute.

Dos Santos made his UEFA Champions League debut on 20 September 2007 during a 3–0 home win against Lyon. He came on as a substitute for Xavi in the 79th minute.

During the 2007 FIFA U-20 World Cup, Mexico was placed in Group C, where they were drawn against Gambia, Portugal and New Zealand. On 2 July 2007, Dos Santos and the rest of the Mexico team played against Gambia and won 3–0, with Dos Santos opening the scoring in the second half with a volley into the top left-hand corner from outside of the box. He then played against Portugal, where Mexico won 2–1, scoring the opening goal from the penalty spot. As Mexico had already qualified from the group, he was rested for the game against New Zealand. In the round of 16, Mexico played against Congo and Dos Santos returned to the starting line-up and yet again opened the scoring with a goal from the penalty spot in a match that Mexico won 3–0. In the quarter-finals, Mexico was eliminated by Argentina by an own goal on the second-half, which was the only goal of the game in a 1–0. Dos Santos was awarded the Adidas Bronze Ball.

Dos Santos earned his first selection for a Mexico senior team roster when Hugo Sánchez picked him for exhibition games against Panama and Brazil. Dos Santos appeared for the first time for Mexico in a 1–0 victory over Panama on 9 September 2007 wearing the number 10 jersey. The match was abandoned at half time because of heavy rain. He scored his first two goals for Mexico on 24 June 2009 in a friendly match against Venezuela, a game in which he was also named Man of the Match.

On 17 May 2008, Dos Santos scored a hat-trick against Real Murcia, with a final score of 5–3, granting a victory to Barça on the team’s last game of the 2007–08 season. It was also the last game Dos Santos played before joining Tottenham Hotspur.

On 18 June 2008, Dos Santos passed a medical and agreed terms to complete his move to Tottenham from Barcelona. Barcelona reported that the transfer fee was €6 million with an additional €5 million payable depending on appearances for Tottenham.

The young Mexican was on target twice as Tottenham beat local Spanish side UD Tavernes in an 8–0 thumping on their 2008–09 pre-season tour. He also played in Spurs’ other pre-season games including the 5–1 wins over Leyton Orient and Norwich City. He also scored the second goal in the 3–0 win over Borussia Dortmund to help Spurs to make it two wins out of two and take home the Feyenoord Jubileum Tournament trophy. He scored his first competitive goal for Spurs in the UEFA Cup on 26 February 2009 against Shakhtar Donetsk. After 12 first team appearances, he was sent on loan to Ipswich Town for the remainder of the season.

In March 2009, Dos Santos signed on loan at Ipswich Town until the end of the season. He made his debut on 14 March 2009, coming on as a substitute against Reading. He scored his first league goal and the equaliser in the following game against Burnley. He scored his second goal against Bristol City on Easter Monday, a 94th-minute penalty to equalise for Ipswich. He also claimed an assist and a goal from the penalty spot in Ipswich’s 3–2 win over local rivals Norwich City a week later. He finished his loan with four goals in eight appearances.

Dos Santos scored his third goal for Mexico on 19 July in the 2009 CONCACAF Gold Cup quarter-final game against Haiti in the 42nd minute and also recorded two assists in the 4–0 victory. On 26 July 2009, he helped Mexico end a ten-year drought of victory against the United States on American soil with a 5–0 victory that helped secure Mexico’s fifth CONCACAF Gold Cup. He was named player of the tournament.

On 5 September 2009, Dos Santos contributed to all three goals in a 3–0 win over Costa Rica in the 2010 FIFA World Cup qualification stages. He scored the first goal from outside the penalty box with his preferred left foot and assisted in the following two goals.

Dos Santos is the son of former Brazilian footballer Zizinho, who played for Mexico clubs América and León in the late 1980s. His mother, Liliana Ramírez, is Mexican. Dos Santos has two brothers and two half-brothers; the elder, Éder, played for América’s reserves team as a defensive midfielder before retiring in 2009, and his younger brother, Jonathan, currently plays for LA Galaxy. Dos Santos has appeared on the cover of the MLS custom editions of FIFA 16 and FIFA 17.

In January 2010, Dos Santos signed for Turkish club Galatasaray on loan for the remainder of the 2009–10 season, with an option to purchase him at the end of that period. The move reunited the player with Frank Rijkaard, his former coach at Barcelona. On 31 January, Dos Santos made his debut coming on as a 58th-minute substitute for Emre Çolak in a Süper Lig game against Denizlispor, a 2–1 victory. He returned to Tottenham in the summer having failed to score for Galatasaray, and stayed there for half a season before being loaned to La Liga club Racing de Santander in January.

At the 2010 World Cup, Dos Santos started in every game for Mexico as a right winger. He completed 138 passes without providing an assist. He was voted runner-up for the FIFA Young Player of the Tournament award, which eventually went to Thomas Müller of Germany.

A quick, skillful and creative player, Dos Santos is capable of playing in several offensive positions. He is usually deployed as a winger or as an attacking midfielder, and has even been used as a supporting striker. A technically gifted playmaker who possesses great flair and dribbling skills, he has been described as a “clever” and “sharp” player who has the capacity to both score goals and create chances for teammates. As a youngster, he drew attention to himself as a precocious talent, and in 2010 he was named by Don Balón as one the 100 best young players in the world born after 1989.

Dos Santos scored and had an assist in Tottenham’s UEFA Europa League group match against Shamrock Rovers on 29 September 2011 at White Hart Lane. On 7 January 2012, he scored a goal and completed an assist for a 3–0 win against Cheltenham Town in the third round of the FA Cup.

On 31 January 2011, Dos Santos joined La Liga side Racing de Santander on loan until the end of the season from Tottenham. He made his debut for his new club on 5 February 2011 as a substitute against Real Zaragoza, drawing the game 1–1. He scored his first goal as a substitute against Villarreal in the 68th minute on 27 February 2011. Dos Santos scored a brace in a 3–2 win league match over Hércules.

Dos Santos was called up to play the 2011 CONCACAF Gold Cup after a good mid-season loan to Racing de Santander. On 9 June 2011, he scored a brace against Cuba in a 5–0 win. In the final match against the United States, he scored in a 4–2 win by dribbling inside the box against goalkeeper Tim Howard and chipping the ball into the top-left corner over Eric Lichaj – that goal was named as the best goal of the tournament.

On 31 August 2012, Dos Santos signed a four-year deal with Spanish outfit Mallorca, being introduced as their new number 9. On 22 October, he made his debut for Mallorca, playing 60 minutes and assisting both goals in a 3–2 away defeat to Sevilla. He played another 60 minutes on 28 October in a 5–0 home defeat to Real Madrid. Dos Santos scored his first goal for Mallorca against Espanyol on 18 January 2013. Though Mallorca would finish the season in 18th place and was relegated, Dos Santos was a mainstay in the squad, amassing 32 total appearances and finished as their top goal-scorer with six goals as well as seven assists.

In June 2012, Dos Santos was called up to play with the Mexico under-23 squad that would participate at the 2012 London Olympics. On 29 July, he started on the bench but later scored his first two goals against Gabon, earning Mexico a 2–0 win. Dos Santos scored his third goal of the tournament on 4 August against Senegal, scoring a crucial tie breaking goal in the 98th minute of extra time to give Mexico a 3–2 lead, which eventually led to a 4–2 win. He was in the starting XI for the semi-final match against Japan and played the first half of the game, but was substituted out for Raúl Jiménez in the 46th minute due to an injury, which ultimately ruled him out of the final against Brazil. Dos Santos was, however, on the bench and watched Mexico defeat Brazil 2–1 at Wembley Stadium.

On 9 July 2013, Dos Santos completed a much speculated move to recently promoted side Villarreal for a reported €6 million. He finished the 2013–14 season with 11 goals and 8 assists, helping the club finish the season in sixth place.

Dos Santos was called up by Miguel Herrera to play the 2014 World Cup. He played in Mexico’s World Cup opener against Cameroon, and on 29 June 2014, opened the scoring in a 2–1 round of 16 defeat against the Netherlands with a left-footed long range strike.

On 15 July 2015, the Major League Soccer club LA Galaxy announced the signing of dos Santos as a Designated Player, in a reported US$7 million deal.

In July 2016, dos Santos was included in the roster for the 2016 MLS All-Star Game. On 21 July 2016, he came off of the bench during the quarter-finals of the U.S. Open Cup, scoring within three minutes of coming onto the pitch. The goal help the Galaxy start a comeback leading to a 4–2 victory over Seattle Sounders to advance to the semi-finals for the first time in ten years.

In July 2017, Dos Santos was included in the roster for the 2017 MLS All-Star Game.

In May 2018 he was named in Mexico’s preliminary 28-man squad for the 2018 FIFA World Cup in Russia, and in June 2018, he was named in the final 23-man squad for the World Cup.

On 1 March 2019, LA Galaxy announced they had exercised its one offseason buyout of a guaranteed contract on dos Santos, thus releasing him from the team.

On 6 July 2019, Dos Santos officially joined Mexican side Club América. He will play in the Liga MX for the first time after reaching a three-year agreement with América, being handed the number 10 shirt. In his first Súper Clasico against Guadalajara on 28 September, dos Santos suffered a thigh injury mid-match following a tackle from Antonio Briseño, with the defender piercing dos Santos’ skin with his studs and leaving a deep gash in his right leg. He was stretchered off the field and immediately taken to a nearby hospital. Club América later released a statement stating the player had suffered a wound in the quadriceps of the right thigh and would require surgery, thereby ruling him out of action for up to six weeks.