Goals in the last 24 minutes from Henrique and Kleber gave Cruzeiro a 4-1 aggregate victory and a place in an all-Brazilian semi-final with Gremio, who went through on Wednesday.
The night turned sour for Sao Paulo, who have won the trophy four times, when they had Eduardo sent off for a second bookable offence a minute before halftime.
Cruzeiro went ahead in the 66th when midfielder Henrique curled a shot from the edge of the box inside the far post.
They increased their lead with a penalty by Kleber after captain Andre Dias blocked a shot with his arm and was sent off nine minutes from time.
Both sides are looking for their third title in South America's equivalent of the UEFA Champions League.
Argentina's Estudiantes, who won the tournament three times in a row from 1968-1970, beat Defensor Sporting of Uruguay 1-0 in La Plata to line up a semi-final against another Uruguayan side, Nacional.
Striker Leandro Benitez scored in the 13th minute to give Estudiantes a 2-0 aggregate victory.
POOR CLEARANCE
Benitez, who squandered a late chance to score again, rammed home a poor clearance of Juan Salgueiro's cross following a good move down the right started by captain Juan Sebastian Veron, whose father Juan Ramon played for the title-winning side.
Defensor had midfielder Carlos Diaz sent off seven minutes from time for a second yellow card offence.
Estudiantes and Defensor, who upset favourites Boca Juniors in the previous round, began the tournament as outsiders and Veron said: "It's nearly 40 years since we had a semi-final.
"It's great for the club, in La Plata," he added, referring to the first leg to be played at home on June 24.
Nacional qualified on Wednesday, becoming the first Uruguayan team to reach the last four since 1988, the year they won the third of their three titles.
