Luis Ruiz's strike in the 35th minute was enough to see Colombia's Nacional to victory on home soil at the Estadio Atanasio Girardot in Medellin on Wednesday.
Orlando Berrio flicked on a header after winning an aerial duel and Ruiz latched onto the ball, looping it over onrushing Sao Paulo goalkeeper Rogerio Ceni 10 minutes before the break.
Ruiz's goal ended his eight-game drought as Nacional - who defeated Cesar Vallejo 2-0 over two legs to advance to the final four - bounced back from their 3-2 loss at Santa Fe in the Colombian Primera A Clausura semi-finals on Sunday.
After suffering back-to-back away losses in the Copa Sudamericana, Sao Paulo - 6-5 aggregate winners against Emelec in the quarter-finals - return to Brazil for the second leg on November 26.