Deportivo de La Coruña obliged and, in October 2006, Oviedo were given a €331,000 compensation by the La Liga club. Adrián’s finest moment of 2006–07 arrived when, on 31 March 2007, he entered Deportivo’s league match at the Camp Nou in the 61st minute, and although FC Barcelona won it 2–1, he managed to score with a clever touch; it was his only league goal of the campaign, in 15 appearances (six starts).

In the 2007 FIFA U-20 World Cup held in Canada, Adrián scored a hat-trick for Spain in the final group stage game against Jordan on 7 July, with all three goals coming in a span of ten minutes late in the first half.

After receiving few first team opportunities during 2007–08, Adrián was loaned to Segunda División strugglers Deportivo Alavés in April 2008. After helping the Basque team avoid relegation with three league goals, he returned to A Coruña to be loaned again on 14 August, this time to newly promoted Málaga CF on a season-long deal.

On 28 September 2008, Adrián netted his first goal for Málaga in a 2–1 home win over Real Valladolid, and appeared regularly throughout the campaign albeit only scoring three times. For 2009–10 he returned to Deportivo, where he began to feature prominently in the starting XI in various offensive positions. On 23 March 2010, he equalized for 10-men – eventually nine – Depor at Sporting de Gijón, in a final 1–2 loss.

Adrián joined Atlético Madrid on 19 July 2011 as a free agent, signing a four-year deal. Nine days later, in his competitive debut, he assisted in both José Antonio Reyes goals in a 2–1 home win against Strømsgodset IF in the season’s UEFA Europa League; in the second leg, he netted the opening goal in a 2–0 success.

In the same competition, on 25 August 2011, Adrián added a brace in a 4–0 away win against Vitória de Guimarães, which ensured Atlético’s qualification for the group stage 6–0 on aggregate. His first league goal came in a 4–0 home success over Racing de Santander on 18 September, heading in the closer from an Arda Turan cross.

Subsequently, he represented the under-21s in two UEFA European Championships. In the 2011 edition in Denmark, Adrián scored a brace in a 2–0 group stage victory over the Czech Republic, adding another in the next match against Ukraine (3–0). In the semi-final against Belarus, he scored the late 1–1 equalizer which took the game into extra time, adding another in that period in an eventual 3–1 triumph; he was awarded the Golden Boot as the highest scorer in the tournament.

Adrián made his full side debut on 26 May 2012 in a friendly with Serbia: after replacing Soldado at half-time, he scored with a header in the 64th minute, and later won a penalty kick which resulted in the final 2–0 in St. Gallen. He was also part of the Olympic team in 2012.

On 17 December 2013, Adrián extended his link with the Colchoneros until 30 June 2018. On 30 April of the following year, he scored his third official goal of the season, starting and netting the opener to help his team win 3–1 at Chelsea and progress to the final of the UEFA Champions League for the first time since 1974.

On 12 July 2014, Adrián signed a five-year deal with Portuguese club FC Porto, who paid €11 million to Atlético Madrid for 60% of his economic rights. He scored his first goal for his new team on 17 September, in a 6–0 win over FC BATE Borisov for the Champions League group stage; it was his only goal in 17 official appearances over his first season.

On 31 August 2015, Adrián returned to Spain and its top division after agreeing to a one-year loan deal with Villarreal CF. After several months on the sidelines with a left leg tendon ailment, he scored his first goal the following 28 February, concluding a 3–0 home win over Levante UD.

On 28 April 2016, Adrián scored the only goal at the Estadio El Madrigal against Liverpool, coming on for Roberto Soldado late into the second half and netting in the 90th minute of the first leg of the Europa League semi-finals. The following January, after few opportunities at Porto, he returned to Villarreal on the same basis for the remainder of the campaign.

On 11 August 2017, Adrián returned to Deportivo on a one-year loan deal. He scored a team and career-best nine goals, but the club was relegated from the top flight after four years.

On 19 October 2018, in a match against amateurs SC Vila Real for the third round of the Taça de Portugal, Adrián netted four times in a 6–0 away rout. He scored his first goal in the Primeira Liga the following 2 March, but in a 1–2 home loss to S.L. Benfica which leapfrogged the hosts to take first place with ten rounds remaining.

Adrián returned to Spain’s top flight on 30 July 2019, with the free agent joining newly promoted CA Osasuna on a one-year contract.