The first match between them in Montevideo produced a 0-0 result, only the second time that each side had failed to find the back of the net at the tournament this year.
Match preview
Sao Paulo did not look like themselves in the opening leg last week, failing to register a single effort on target despite having 65% of the possession.
On the positive side, however, they have been very compact defensively in the Libertadores, posting three successive clean sheets in this tournament.
In the opening phase of this competition, they went undefeated at Estadio de Morumbi, and did not concede a single goal over that stretch.
Luis Zubeldia's men are currently on a two-match winless run across all competitions, losing domestically to arch-rivals Palmeiras 2-1 on Sunday.
Sao Paulo have not lost any of their last eight competitive fixtures when scoring the opening goal, emerging victorious in seven of those instances.
Tricolor Paulista have not been eliminated from a Libertadores round of 16 tie since 2015, when Cruzeiro beat them on penalties to advance.
A Nacional backline that had been relatively inconsistent in the opening phase of this tournament, conceding seven goals, held firm in the first match of the knockout stage.
It was just the second time the Uruguayans maintained a clean sheet at the Libertadores this year, with the previous time being away from home versus Deportivo Tachira in the group stage last May when they won 1-0.
Nacional are in the exact same position they were in the last 16 a year ago, and on that occasion, they followed up a 0-0 draw with Boca Juniors with a 2-2 result in Argentina, only to be knocked out 6-4 on penalties.
Martin Lasarte's men lost two of their three away encounters in the group portion of this competition, squandering a 1-0 advantage versus Libertad on matchday six (2-1 defeat).
The Uruguayans have failed to emerge victorious in normal time on three successive occasions in all competitions, playing to a 3-3 draw with River Plate from Uruguay in league play last Sunday.
Bolso have never beaten a Brazilian side in the knockout portion of this tournament, with their previous Libertadores away victory against a Brasileiro Serie A opponent taking place in 2019 in Belo Horizonte versus Atletico Mineiro (1-0).
Sao Paulo Copa Libertadores form:
W
W
W
D
W
D
Sao Paulo form (all competitions):
W
W
D
W
D
L
Nacional Copa Libertadores form:
L
W
D
W
L
D
Nacional form (all competitions):
Team News
Last week, Sao Paulo did not have Pablo Maia available due to a thigh issue, Alisson sat out with a broken ankle and Erick did not feature because of muscle tightness.
Patryck is not expected to see the field until early September with a shoulder strain, while Liziero should return around that same time from a hip injury.
In the first leg, Nacional were missing Christian Ebere, who is recovering from knee surgery, while Gonzalo Carneiro and Renzo Sanchez are still out with cruciate ligament tears.
Diego Polenta was one of three newcomers in their starting 11 last week who did not feature in their matchday six defeat versus Libertad (2-1), as he, Sebastian Coates and Diego Zabala replaced Juan Izquierdo, Franco Romero (now with Sporting Cristal) and Gaston Gonzalez.
Sao Paulo possible starting lineup:
Rafael; Rafinha, Arboleda, Franco, Welington; Bobadilla, Gustavo; Araujo, Luciano, Ferreira; Calleri
Nacional possible starting lineup:
Mejia; Lozano, Coates, Polenta, Baez; Sanabria, Oliva, Pereyra; Galeano, Betancourt, Zabala
We say: Sao Paulo 1-0 Nacional
For as sharp as Nacional were defensively in the opening leg, we have difficulty believing they can replicate that against a side in Sao Paulo who are equally strong on the back end at home and have plenty of experience to draw upon in these must-win games.