He began his career at Alavés, but went on to spend most of it at Athletic Bilbao, making over 550 official appearances and winning the 2023–24 Copa del Rey as well as two Supercopa de España titles with the club.

He made his club debut on 6 August in a 2–1 win at BSC Young Boys in the UEFA Europa League (2–2 aggregate, victory on the away goals rule), as a starter.

[5] Ten days later he opened the scoring against FC Barcelona in the season's Supercopa de España,[6] as the Basques eventually lost 2–1 at home and 5–1 on aggregate.

[7] Having been signed initially for the reserve squad, de Marcos had more impact than expected – as did 16-year-old Iker Muniain – making 29 official appearances during 2009–10 and scoring three goals.

[8][9] On 17 December 2011, de Marcos played roughly one hour of the league fixture against Real Zaragoza (2–1 home win) with a tear in his scrotum, which later required 25 stitches.

[36] On the opening matchday of 2023–24 (a 2–0 loss to Real Madrid at San Mamés), de Marcos made his 500th appearance for Athletic, aged 34, becoming only the seventh player to do so.

[41] In November 2015, de Marcos and Nacho were called up into the Spain squad as replacements for the injured Sergio Ramos and Juanfran, ahead of friendlies against England[42] and Belgium.