After spending seven years with Real Madrid, playing for its various teams, he made a name for himself in La Liga with Villarreal, appearing in 230 official games over the course of five seasons.

However, as fifth-placed RCD Mallorca were expelled from European competition due to bankruptcy, the Valencians took their place in the qualifying rounds of the UEFA Europa League.

[13] On 25 January 2013, López returned to Real Madrid after Casillas suffered a hand injury which ruled him out for 12 weeks, signing for €3.5 million until June 2017.

[16] On 5 March, he made a string of saves as Real beat Manchester United 2–1 at Old Trafford to qualify for the last-eight in the Champions League (3–2 on aggregate); after the match, coach José Mourinho said: "Diego López was the best player in my team".

[19] He made his competitive debut on 31 August in the first match of the new season in Serie A, saving a late penalty from Antonio Candreva in a 3–1 win over SS Lazio.

[25] He was overtaken by Pau López still under manager Quique Sánchez Flores,[26][27] but after the latter moved to Real Betis, he regained his starting role and was the only player to feature in all 38 games of 2018–19.

[33] He was named in the squad by manager Vicente del Bosque for the 2009 FIFA Confederations Cup in South Africa behind Casillas and Pepe Reina, and did not play any matches there.

[34] López earned his only cap on 12 August 2009, playing the last 30 minutes of a 3–2 friendly win in Macedonia, replacing Reina and not conceding any goals.

[36] López was a commanding and well-rounded goalkeeper, with a large and imposing physique, strong leadership qualities and good handling, which facilitated him in coming out to claim crosses.