As a player, he was nicknamed El Maestro, and was best known for his two spells with Racing de Santander, starting and finishing his 19-year professional career at the club.

Starting in January 2020, he was in charge of Barcelona for seven months, being dismissed following an 8–2 loss against Bayern Munich in the UEFA Champions League.

[8] He enjoyed a good first two seasons,[9] but appeared rarely in his last after some spats with elusive club chairman Jesús Gil.

[14] Setién appeared three times for Spain and was selected for the 1986 FIFA World Cup squad, but did not leave the bench during the tournament in Mexico.

[16] Setién began working as a manager on 5 October 2001, succeeding the dismissed Gustavo Benítez at a Racing side that had started poorly following relegation to Segunda División.

[17] He took the team from 17th to promotion as runners-up to Atlético, but left at the end of the season due to pressure and handed the reins to his former teammate Manuel Preciado.

[29] On 18 March 2017, Setién announced that he would leave the Canary Islands club at the end of the campaign due to disputes with the board.

[34] Setién signed as head coach of Barcelona on 13 January 2020, replacing the dismissed Ernesto Valverde on a contract lasting to June 2022.

On 14 August 2020, they lost 8–2 to Bayern Munich in the quarter-finals of the UEFA Champions League,[39] which was the first time in 74 years that the club had conceded eight goals in a game;[40] it was also the first loss by a six-goal margin since 1951.

[48] His father-in-law José Antonio Lozano played in the Spanish second tier in the early 1960s, and all three relatives represented Racing Santander.