His first club was Estoril-Praia, where he remained until 1994. With Santos as a coach, Estoril climbed up two categories and reached Portugal's top football division.
In 1994 he took over C.F. Estrela da Amadora, and in 1998 he moved to FC Porto, winning the national championship and Portuguese Supercup in his first season. He was the last of the coaches to win in FC Porto's run of 5 consecutive championships, the longest ever in Portuguese club history. For that, he is known as "the engineer of the penta". Next season Porto missed the 6th title in the last round to Sporting Portugal but won the Portuguese Cup and Supercup, also reaching the UEFA Champions League quarter–finals.
In 2001 Santos took over AEK Athens FC, leading the club to the conquest of Greek Football Cup, and losing the championship from Olympiacos FC due to goal average. His next step was Panathinaikos FC, taking over the reins of hometown Sporting Clube de Portugal for 2003-04. The next season, he returned to AEK and the team, based on young players, reached the Greek Cup semi-finals and finished third (only three points behind the first) in the league.
On May 20, 2006 it was announced that Santos would coach Sport Lisboa e Benfica for the 2006-07 season. That season Benfica finished third, missing the opportunity to be in the Champions League directly, giving just one point to the second place and two to the eventual winners FC Porto. In the following season, he spent the whole pre-season with Benfica, in which he would lose the services of team captain and best goalscorer Simão Sabrosa who was transferred to Spanish team Atlético Madrid. Shortly after, Santos was sacked by Benfica's board on 20 August 2007, after a draw against Leixões S.C. in the first match of 2007-08. He was replaced by Spanish coach and former Benfica manager José Antonio Camacho.