The RFEF announced earlier on Thursday that Luis Enrique would not carry on in the role after the World Cup elimination to Morocco in the last 16.
A separate statement then confirmed that U21 coach De la Fuente would replace him.
Luis Enrique took over in 2018 after Julen Lopetegui left for Real Madrid and led Spain to the semifinals at Euro 2020, losing to eventual winners Italy.
At this year's World Cup in Qatar he helped Spain out of the group, with Germany knocked out in the process, but then lost on penalties to Morocco.
With his contract expiring this month, the RFEF said the decision had been made to start a new project with a new person in charge.
De la Fuente, 61, has been coaching Spanish youth teams since 2013, working first with the U19s before taking the U21 post in 2018.
He also took charge of an U23 side at the Olympics in Tokyo last summer, losing to Brazil in the final to win a silver medal.
In that role, as well as his position with the U21s, he has worked with a number of the players currently involved with the Spain senior side, including the likes of Pedri, Ansu Fati and Alejandro Balde.
Born in Haro, La Rioja, de la Fuente graduated from Athletic Bilbao's youth system, and made his senior debut with the reserves in 1978, in Segunda División B. On 8 March 1981 he made his first-team – and La Liga – debut. In July 1987, de la Fuente moved to fellow league club Sevilla FC. De la Fuente joined Deportivo Alavés in 1993, with the side in the third tier. After one season, he retired at the age of 33.
De la Fuente's first managerial job was at Club Portugalete, in the regional leagues. In summer 2000 he was appointed at Segunda División B club CD Aurrerá de Vitoria, but was sacked in March. After a spell back at Sevilla, de la Fuente returned to Athletic. Initially a manager of the reserves. On 13 July 2011, de la Fuente was named Alavés coach, being dismissed on 17 October. On 5 May 2013 he was appointed at the helm of the Spain under-19 team, who won the 2015 UEFA European Championship in Greece. De la Fuente became manager of the under-21 side in July 2018.
De la Fuente was also in charge of the Spanish Olympic team at the delayed 2020 games in Japan. His side won the silver medal, losing 2–1 to Brazil in the final.
