Prior to the start of the 2000–01 Bundesliga season, Santa Cruz scored in a semi-final 4–1 win against 1. FC Kaiserslautern in the 2000 DFB-Ligapokal on 30 July. During the final, he was substituted off the field for Carsten Jancker after just 46 minutes as Bayern Munich defeated Hertha BSC 5–1 on 1 August. Santa Cruz scored his first goal of the season, eight minutes after being substituted on for Alexander Zickler on the 11th minute, in a 3–0 away win to VfL Bochum on 19 August. On 19 September, in his first appearance of the 2000–01 Champions League, he was substituted onto the field after 46 minutes and then substituted off the field after 73 minutes. Four days later, he scored the winning goal in a 2–1 away victory to 1. FC Köln on 23 September. After suffering from an injury, he returned to action on 17 December to score the first goal of the game after 15 minutes in a 3–1 away win to Hertha BSC, he played 89 minutes of the match before being substituted off. He then missed the following nine games, where on his return he scored Bayern Munich's first goal after six minutes of the game in a 1–1 draw to Borussia Dortmund on 7 April. He missed a large amount of the Champions League, he made his return where he was brought onto the field for Giovane Élber on 65 minutes in the second-leg quarter-final 2–1 win against Manchester United on 18 April. Due to injuries he was reduced to only 19 league appearances for the season, having scored five goals, as Bayern Munich claimed both the Bundesliga and the UEFA Champions League titles, where he was an un-used substitute during the final on 23 May. Santa Cruz finished the season with six goals in 28 matches.