The Uruguayan are in outstanding form heading into the knockouts and seek to notch an encouraging result against the three-time continental champions.
Match preview
Nacional were far from convincing in the Copa Libertadores group stage but much has changed since they managed to advance from their section.
Bolso claimed three wins from six to progress, losing twice and playing out one draw, with eight goals scored and seven conceded underscoring their average form.
The turnaround since Martin Lasarte replaced Alvaro Recoba in mid-June has been evident, with Nacional undefeated since the managerial change, claiming five wins in seven excluding penalty shootouts.
The Montvedio outfit did flourish on home soil in the competition's group stage, claiming two wins from three with only undefeated group winners River Plate preventing Bolso from securing maximum points in a 2-2 draw.
Lasarte will back his team to continue their undefeated form under his management, keen to claim a positive result heading into next week's match in Brazil.
Their opponents may not be going into their last-16 tie with the same momentum, but Sao Paulo's four-game unbeaten run should count for much on Thursday.
Even more noteworthy of the Brazilian side's form is the ongoing sequence of games without conceding, with Luis Zubeldia's troops keeping four consecutive shutouts through their run.
Four matches without losing follow the club's three-match winless sequence without maximum points (two points) where they failed to find the back of the net in a home draw with Juventude and a 1-0 loss to Fortaleza.
Only Goias have prevented Tricolor Paulista from scoring during their ongoing run, a blemish that is disregarded when considering Zubeldia's men held a 2-0 advantage in the domestic cup's last-16 first leg.
Having notched six away points to end group winners in their section, Sao Paulo will aim to extend their commendable road form against a side pulling up trees heading into the first knockout round.
Nacional Copa Libertadores form:
W
L
W
D
W
L
Nacional form (all competitions):
W
D
W
W
W
D
Sao Paulo Copa Libertadores form:
L
W
W
W
D
W
Sao Paulo form (all competitions):
D
L
W
W
D
W
Team News
Nacional are not expected to have Christian Ebere, Renzo Sanchez and Gonzalo Carneiro for Thursday's match and potentially both legs due to the trio's knee injuries.
Without Carneiro's goals, the home side will hope Alexis Castro makes the difference from midfield having notched two group-stage goals and three in his last four appearances under Lasarte.
Sao Paulo's Igor Vinicius is doubtful with a knock while Giuliano Galoppo is touch-and-go with a foot bruise.
However, Alisson Castro (ankle) and Pablo Maia (hamstring) are not anticipated to play any part for the Brazilian side on Thursday.
Jonathan Calleri and Luciano scored three goals apiece in the group phase, and the away side will hope they carry that goalscoring form into the knockouts.
Nacional possible starting lineup:
Mejia; Lozano, Izquierdo, Polenta, Baez; Oliva; Galeano, Magole, Castro, Zabala; Santander
Sao Paulo possible starting lineup:
Rafael; Rafinha, Arboleda, Franco, Welington; Moura, Bobadilla, Gustavo, Nestor; Luciano, Calleri
We say: Nacional 1-1 Sao Paulo
Nacional have netted in seven straight matches heading into their Libertadores match with Sao Paulo, pointing to them halting the Brazilian side's run of clean sheets. However, the spoils could be shared between the in-form sides that have given little away heading into this week's first leg.