Cazorla then progressed through the reserve side, making his debut with the first team on 30 November 2003 in a 1–0 La Liga win at Deportivo de La Coruña, playing one minute in place of Roger, making one more appearance off the bench over the season. He scored his first goal in a 3–0 win at Odense Boldklub in the following summer’s UEFA Intertoto Cup, which the Yellow Submarine eventually won.

Established in the main squad in the 2004–05 campaign, Cazorla scored four goals in a run to the quarter-finals of the season’s UEFA Cup. On 1 May 2005, given an opportunity due to Juan Román Riquelme’s suspension, he scored his first league goal in a 4–0 win over Getafe at El Madrigal, and followed it a week later with a strike in a 2–0 victory at Málaga. After contributing to an eventual fourth-place finish, he also made two goalless appearances in the following season’s UEFA Champions League, where Villarreal were semi-finalists.

On 7 July 2006, newly promoted Recreativo de Huelva signed Cazorla for €600,000 on a four-year deal, with a clause in his contract whereby he could return to Villarreal (for €1.2 million), going on to score in his official debut, a 1–1 home draw with Mallorca, on 27 August. The following 22 April, he dedicated a goal to his father, José Manuel, who had died recently, in a 4–2 home win against Racing de Santander; in the penultimate fixture on 10 June, he struck twice in a 5–2 win at Deportivo de La Coruña.

On 26 August 2008, Cazorla announced that Real Madrid were interested in signing him. He then went on to cause a stir in the media by rejecting the team, announcing that, “There are many other things in football besides Real Madrid. It’s clear that it is possible to say ‘no’ to them, there is no doubt that they are a great team, but I also feel very satisfied and valued at my club.” He added, “I hope I can continue growing at Villarreal because I am young and I’m only starting off with the national team.”

On 17 May 2008, senior side boss Luis Aragonés surprised the Spain’s press by including the uncapped Cazorla and Sergio García in his UEFA Euro 2008 squad, over more established wingers such as Joaquín and Albert Riera. Justifying the decision, Aragonés stated, “They are players [Cazorla and García] who are performing very well and had the possibility of coming. I made myself decide between Riera and Cazorla where I considered each player’s form.”

After making his debut on 31 May 2008 in a 2–1 friendly win over Peru, Cazorla made substitute appearances in the tournament’s group stage matches against Russia, Sweden and Greece, also coming from the bench in the quarterfinals against Italy, converting his penalty in the ensuing shootout which Spain won. In the final, he played the last 25 minutes for David Silva, as Spain defeated Germany 1–0 and aided his country in winning their first major tournament in 44 years.

On 19 November 2008, Cazorla scored his first international goal against Chile, a 3–0 friendly win at his club’s home ground. He was summoned for the following year’s FIFA Confederations Cup, where he made a couple of substitute appearances.

On 26 July 2011, Cazorla left Villarreal and returned to Andalusia to join high-spending Málaga for a fee of €21 million. He scored on his official debut on 28 August, netting from a superbly taken free kick in a 1–2 away loss against neighbouring Sevilla. On 12 September, he scored a brace and gave an assist in another local derby, a 4–0 home win against Granada, and netted his fourth in only four games nine days later – again from a free kick – in a 1–0 home success over Athletic Bilbao.

After missing the 2010 FIFA World Cup due to a hernia, Cazorla returned to the national team’s setup. On 4 June 2011, during the first half of a friendly against the United States in Foxborough, Massachusetts, he scored twice in a 4–0 win.

On 18 March 2012, Cazorla scored from an injury-time free kick in a 1–1 away draw against Real Madrid, and finished the season as the team’s second top scorer (only behind Salomón Rondón) as Málaga finished fourth and qualified for the Champions League for the first time in the club’s history.

On 7 August 2012, it was officially announced that Cazorla had signed a long-term deal with Premier League club Arsenal, worth £10 million. He became Arsène Wenger’s third major signing of the summer after the arrivals of German attacker Lukas Podolski and French striker Olivier Giroud. Cazorla picked up the man of the match award on his debut for the club against Sunderland.

In November 2012, along with fellow Premier League stars Michu and Juan Mata, he bought shares in former club Oviedo as they struggled to raise €2 million to stay afloat in the Spain’s third division.

On 14 May 2013, Cazorla assisted all four of Arsenal’s goals in a vital 4–1 win over Wigan Athletic, which relegated their opponents and kept the Gunners in fourth place, with the eventual qualification to the Champions League. Cazorla finished an exceptional first season in England as the only Arsenal player to feature in all 38 league games, and on 31 May 2013, he was named Arsenal’s Player of the Season for 2012–13. He ended his first season at Arsenal with 12 goals and 14 assists from 49 appearances. “I think he is a bit of an underrated player in the Premier League,” Wenger told Arsenal. “When you think he was not in the [PFA] team of the season picked by the players, it’s quite harsh. Personally I would have put him in there.”

Cazorla returned to pre-season training a few weeks later than normal after his involvement in the Confederations Cup for Spain. He started from the bench against Aston Villa but was introduced at half-time after Alex Oxlade-Chamberlain’s injury. He played in every minute of Arsenal’s games after that and played an important part in the side’s three-straight wins early on in the season. The Spaniard picked up an ankle injury in September before the Sunderland game that kept him out of action for the rest of the month. On 30 November 2013, Cazorla made his 300th career top-flight league appearance, when he started for Arsenal in a 3–0 win against Cardiff City.

Cazorla tucked home the winning penalty in the shootout against Wigan to send Arsenal to the final of the FA Cup at Wembley Stadium. The Spaniard also added to his assist tally when his corner was headed home by Giroud against West Brom and scored Arsenal’s first goal – a direct free-kick – as the team came from 2–0 down to defeat Hull City 3–2 in the 2014 FA Cup Final, winning his first piece of silverware with the club. He finished the campaign with 7 goals and 47 appearances in all competitions.

Cazorla began the 2014–15 campaign with another goal at Wembley, slotting home Arsenal’s opener against Manchester City in the 2014 FA Community Shield. On 30 May 2015, Cazorla was selected to start in the 2015 FA Cup Final, playing the full 90 minutes and being voted man of the match in a 4–0 defeat of Aston Villa at Wembley. He finished the Premier League season with 11 assists, the second-highest in the League behind Chelsea’s Cesc Fàbregas, and seven goals.

Cazorla began the 2015–16 season strongly, featuring in every match for Arsenal from the start of the campaign, with analysis showing him to be the league’s busiest and most accurate passer. However, on 30 November 2015 he suffered a knee injury in a match against Norwich City and was ruled out for at least three months. In fact he did not return to the team until the last matchday on 15 May 2016, when he was named as player of the match in a 4–0 win over relegated Aston Villa which secured runners-up spot for the Gunners.

On 9 October 2015, Cazorla scored twice in a 4–0 win over Luxembourg at the Estadio Las Gaunas in Logroño, a result which sent Spain to Euro 2016. He played and scored in a friendly victory over England the following month, but was not selected for the Euro 2016 finals squad having just come back from injury, and did not feature for his country in 2016 or 2017 due to further long-term injury problems.

At the outset of 2016–17 Cazorla was once again an important player for Arsenal, making 11 appearances and scoring twice, before he injured his right Achilles tendon during a Champions League fixture against Ludogorets Razgrad on 19 October 2016, sustaining the injury from a challenge while providing an assist for a Mesut Özil goal in the 6–0 victory. Standard rehabilitation did not prove effective and in December it was confirmed that he would require surgery. He eventually endured eight operations on the problem (the ankle originally having been damaged playing for Spain in 2013), and contracted gangrene on the affected area with the infection ‘eating’ part of the tendon. It had been feared that he could be unable to walk again or could even lose the affected leg. The condition required antibiotic treatment and a skin graft, with the skin sourced from Cazorla’s left forearm where a tattoo of his daughter’s name had featured. He temporarily relocated to Salamanca to complete a further recovery programme, with the aim of returning to play football in 2018; after further operations, however, this was revised to 2019.

He has a son, Enzo, and a daughter, India; their names were tattooed on his forearms, which he would kiss after scoring goals, although the design on his left arm was ruined in 2017 when the skin was needed for use on a graft over his infected right heel.

After his departure from Arsenal, Cazorla spent a brief period training with the youth team at Alavés. He then returned to former club Villarreal in order to train with them during the rest of the pre-season period and prove his fitness. He played his first game in 636 days when he appeared in a friendly against Hércules. He came on as a substitute in the 57th minute to a standing ovation. On 9 August 2018, his signing was officially announced by the club.

Cazorla scored his team’s second goal in a 5–1 thrashing of Real Betis on 27 September 2019. With this goal, he became the highest-scoring midfielder in Villarreal’s history with 46 goals, a record previously held by Juan Román Riquelme. He ended the season with 10 assists, the third-most in the league.

Having overcome his injury problems and returned to playing regularly at Villarreal, in May 2019 Cazorla was recalled to the Spain squad for upcoming UEFA Euro 2020 qualification fixtures. On 7 June, he made his first appearance for Spain since November 2015, a gap of 1302 days, when he started in a 4–1 UEFA Euro 2020 qualifying win over Faroe Islands. It was also a milestone occasion for Cazorla as he captained the national team for the first time in the second half of the match, assuming the armband following the substitution of regular captain Sergio Ramos.

With his contract ending at the end of the 2017–18 season, it was announced that Cazorla would be leaving Arsenal. In 2020, he voiced his desire to return to Arsenal for a farewell match.

On 19 July 2020, Cazorla made his last appearance for Villarreal, in a 4–0 league win over Eibar. Before being substituted in the 82nd minute of the match, he assisted the opening goal, which was scored by André-Frank Zambo Anguissa. He ended the season with 11 goals (joint 10th most) and 9 assists (the third-most) in the league. Cazorla was given a guard of honour by teammates and opponents as he exited the pitch.

On 20 July 2020, Al Sadd confirmed that Cazorla joined the club to play under his former teammate Xavi. On 30 August, Cazorla scored on his debut match in a Qatari Stars Cup semi-final win against Al Ahli. This followed with a brace four days later on the 2020–21 QSL matchday one fixture against Al-Kharaitiyat.