However, the visitors to Morumbi will move to within two points of the Group D leaders if they can record a surprise victory over the Brazilian giants.
Match preview
While Sao Paulo only find themselves in eighth position in the league right now, Tricolor Paulista are enjoying a fine campaign in all competitions.
Until their recent back-to-back defeats, Sao Paulo had put together a 12-match undefeated streak with eight wins being recorded during that time.
As it stands, it remains to be seen whether their double losses versus Sport Recife - in a Copa do Brasil that they won on penalties - and Gremio in the league will hinder them in the long term.
Nevertheless, Dorival Junior's side are enjoying an excellent Copa Sudamericana campaign, collecting 10 points and four clean sheets from their opening four group-stage fixtures.
Holding a five-point lead over their next opponents who are third, Sao Paulo are on the brink of guaranteeing at least a knockout-round playoff spot, yet Dorival Junior knows that they can ill-afford any complacency against resolute opponents.
Sitting out of the qualification places as it stands, it would be easy to write off Deportes Tolima, but this is a side that have kept shutouts in three of their four matches.
Their solitary defeat came by a 2-1 scoreline at home to Tigre, with the last two continental games against Sao Paulo and the reverse fixture away at Tigre ending goalless.
Juan Cruz Real's side have work to do to qualify for the last 16, but they are unbeaten in five games in all competitions, albeit four of those contests ending in draws.
El Vinotinto y Oro are all the way down in 13th spot in the Colombian top flight, though, and they need a notable result to give their season the kick-start that it needs.
Sao Paulo Copa Sudamericana form:
W
W
D
W
Sao Paulo form (all competitions):
W
W
W
W
W
L
Deportes Tolima Copa Sudamericana form:
W
W
L
D
D
Deportes Tolima form (all competitions):
L
W
W
L
D
D
Team News
Jonathan Calleri is expected to start for Sao Paulo after netting his sixth goal of the season in all competitions at the weekend.
Dorival Junior switched to a back three which did not work out against Gremio, and it may see the Sao Paulo boss revert to a back four.
Patryck and Rodriguinho could be among the players who are handed an immediate recall, as may Marcos Paulo on the left flank.
Tolima are without midfielder Fabian Mosquera after his red card versus Tigre, with Juan Valencia or Juan David Rios in line to deputise.
The remainder of the team could stay the same, although Brayan Gil Hurtado could return down the centre of the attack.
Sao Paulo possible starting lineup:
Rafael; Ramos, Costa, Franco, Patryck; Luan, Rodriguinho; Araujo, Rato, Paulo; Calleri
Deportes Tolima possible starting lineup:
Volpi; Riascos, Arboleda, Cuenu, Hernandez; Valencia, Nieto; Arango, Guzman, Lucumi; Herazo
We say: Sao Paulo 1-0 Deportes Tolima
Tolima have already shown during the group stages that they are capable impressing against the most illustrious teams in the group. Nevertheless, while we feel that only one goal will be netted in this contest, it could come for the home side, securing a potentially-decisive result for both clubs.