Isco appeared with Spain’s U17 in 2009 FIFA World Cup, scoring three times in the process as the nation finished third. In 2011 he represented his country – together with Málaga teammate Recio – in the U-20 World Cup held in Colombia, netting one goal in an eventual quarter-final exit.

While still registered with the reserves, Isco made his debut with the first team on 11 November 2010, against UD Logroñés for the campaign’s Copa del Rey, scoring two goals in a 4–1 home win (Paco Alcácer made his senior bow in the same fixture). He played his first La Liga match three days later, featuring for 20 minutes in a 2–0 home win against Getafe CF after coming on as a substitute for Aritz Aduriz; he thereafter made three further league appearances and two in the UEFA Champions League, all from the bench, and helped the B-team return to the third level by scoring 15 goals in their campaign.

In mid-July 2011, Isco signed a five-year contract with Málaga CF after the club activated his buy-out clause of €6 million. He scored his first goal for his new team on 21 November 2011, starting in a 3–1 away win against Racing de Santander; he netted again the following week in a 2–1 win against Villarreal CF, and finished his first season with 32 games and five goals as the side qualified for the UEFA Champions League for the first time in its history.

Includes 2011 Tercera División play-offs, Supercopa de España, UEFA Super Cup and FIFA Club World Cup.

On 18 September 2012, in Málaga’s first game in the Champions League group stage, Isco netted twice in a 3–0 home win over FC Zenit Saint Petersburg, also being chosen as Man of the Match. On 22 December he scored the first goal in an eventual 3–2 win against Real Madrid at La Rosaleda, leading the locals to their first victory over that opponent in 29 years; in December he won the Golden Boy award, beating Stephan El Shaarawy and Thibaut Courtois.

On 28 February 2012 Isco was called to the Spain under-23s team for a friendly against Egypt, but did not leave the bench. On 15 May he was picked for the first time to the senior team for friendlies with Serbia and South Korea, but took no part in either match. In July, he went with the under-23 team to the Olympics in London, starting all of Spain’s matches as they were eliminated without scoring a goal.

On 28 January 2013, Isco ended speculation regarding his future by signing a new contract with Málaga – his new buyout clause was set at €35 million. He scored his eleventh goal of the campaign on 13 March, netting the opener in a 2–0 home win against FC Porto, good enough for last-eight qualification after the 0–1 loss in Portugal.

On 17 June 2013, Isco confirmed that he had received offers from Real Madrid and former Málaga manager Manuel Pellegrini’s Manchester City, but stated he would only make a final decision on his future after the UEFA European Under-21 Championship final. On 26 June, Real Madrid president Florentino Pérez confirmed that a deal had been reached with the player and that he would be presented by the club next week, once he passed his medical; the following day he signed a five-year contract, with Real Madrid paying €30 million for his services, thus becoming the first signing of newly appointed manager Carlo Ancelotti.

On 18 August 2013 Isco made his official debut for the Merengues, recording an assist and scoring the winning goal in a 2–1 home win over Real Betis, the latter coming through an 85th-minute header. He continued with his form by netting two goals against Athletic Bilbao on 1 September (3–1, also at the Santiago Bernabéu).

On 6 February 2013 Isco made his debut with the main squad, playing the last 30 minutes in a 3–1 win over Uruguay in Doha, Qatar. Also that year he appeared at the UEFA European Under-21 Championship in Israel, he scored in the final and finished the competition with the Bronze Boot (3 Goals) and made the team of the tournament as a key player for the eventual winners.

In 2013, Isco was credited by Marca journalist Pablo Polo as being “the most promising young player in Spanish football”, comparing his strength, skill, and low centre of gravity to Sergio Agüero, and his vision and passing abilities to Zinedine Zidane. Former Real Madrid captain Iker Casillas predicted in 2015 that Isco would become Spain’s most important player.

Isco started the first game of the 2014–15 season against Real Sociedad, and scored the first in a 4–1 win against UD Almería on 12 December 2014. He was a regular starter in the club’s FIFA Club World Cup winning campaign, scoring the last in a 4–0 semi-final routing of Cruz Azul. His performances over the season earned him many plaudits, and he was compared to Zinedine Zidane by the French legend himself.

Isco scored his first international goal for Spain in a UEFA Euro 2016 qualifying match against Belarus in Huelva on 15 November 2014, opening a 3–0 win.

Prior to the start of the 2015–16 season, Isco switched his shirt number from 23 to 22, which he had previously worn at Málaga. On 21 November 2015, as Real lost 0–4 at home to FC Barcelona in El Clásico, he was sent off in the 84th minute for a foul on Neymar. He scored twice on 2 December, as the team won 3–1 at Cádiz CF in the first leg of the last 32 of the domestic cup. Isco was a part-time starter when the team won the 2015–16 UEFA Champions League.

On 11 February 2017, Isco scored Real Madrid’s 100th goal of the season as he attained the game-winning goal in a 3–1 away victory against Osasuna.

On 8 August 2017, Isco scored a goal in the 2017 UEFA Super Cup, contributing to Real Madrid’s 2–1 victory against Manchester United. His performance earned him the man of the match award.

On 14 September 2017, he signed a new deal with Real Madrid until June 2022. During the 2017–18 UEFA Champions League, he made eleven appearances, when Madrid won their third consecutive and 13th overall Champions League title.

Isco scored his first hat-trick for Spain on 27 March 2018, netting three goals against Argentina in a 6–1 friendly win.

In May 2018, he was named in Spain’s final squad for the 2018 FIFA World Cup.