In July 2009, de Marcos went straight into La Liga, penning a four-year deal with Athletic Bilbao for about €350,000. He made his club debut on 6 August in a 2–1 win at BSC Young Boys in the UEFA Europa League, as a starter; ten days later he opened the score against FC Barcelona for the season's domestic Super Cup, as the Basques eventually lost 1–2 at home and 1–5 in total. 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 the 2009–10 campaign and scoring three goals. He played his only match with the B-team on 14 April 2010 against Zamora CF, in a season where they narrowly avoided relegation from division three. De Marcos appeared less in his second season, but was also used as a full back by manager Joaquín Caparrós, finishing the year with 15 games in all competitions. The following campaign, under Marcelo Bielsa, he played in that position and also in central midfield. On 17 December 2011, de Marcos played roughly one hour of the league fixture against Real Zaragoza with a tear in his scrotum, which later required 25 stitches. On 4 January of the following year he extended his contract with the Lions until June 2016, with a release clause of €32 million. De Marcos netted in both legs of the 2011–12 Europa Leagueround of 16 against Manchester United, as Athletic won both games and went through 5–3 on aggregate. He also scored in the next round against FC Schalke 04, playing in a total of 15 ties to help his team reach the final; they also made it to the decisive match in the domestic cup, losing to Barcelona. On 13 October 2014, de Marcos agreed to a new three-year extension until 30 June 2019, with a buyout clause being set at €40 million. He also featured in all ten matches in both the UEFA Champions League and Europa League, but did not take part in the 2015 Spanish Cup final due to suspension ; he did play the full 180 minutes of the 2015 Supercup, in which his club finally overcame the same opponent. Following the departure of veteran Andoni Iraola, de Marcos became the regular right-back in Ernesto Valverde's line-ups. In November 2016, he suffered an injury to his left foot which caused him to miss two months of action. On his first start since recovering on 22 January 2017, he scored in a 2–2 draw at home to Atlético Madrid, regaining a starting place for the remainder of the season. On 20 August he received another significant injury, a sprain to his left ankle in the opening fixture of the domestic campaign against Getafe CF; three months later he returned, starting in a 2–2 draw away to Deportivo La Coruña on 26 November, although he lasted less than an hour before being substituted with an injury once more – this time a problem with his right foot. In July 2019, de Marcos reached the milestone of ten years with the same club. An injury to his left ankle ligaments forced him to miss much of 2019–20, but he was able to return after the delay caused by the COVID-19 pandemic in Spain.
Outside football, de Marcos is known for his humanitarian work, including non-publicised visits to see sick children in local hospitals on a weekly basis and frequent charity visits to Africa and South America, in addition to occasionally offering lifts in his car to supporters who attended training sessions at Lezama on foot. In 2019, he authored a short book in collaboration with Athletic Bilbao's community foundation, describing the high and low points of his first year at the club which were followed by a trip to the West African country of Togo which helped him put his newfound fame as a sportsman in perspective.
