The hosts take a 2-1 advantage to Montevideo and are looking to reach the quarter-finals of this competition for the first time in their history.
Match preview
After losing 2-0 to Nacional in the Uruguayan Apertura earlier this month, Penarol got their revenge in the first leg last week, thanks to strikes from Agustin Canobbio and Valentin Rodriguez.
Head coach Mauricio Larriera will, however, be slightly disappointed that his side could not hold onto their two-goal cushion, as Gonzalo Bergessio pulled one back in the 95th minute to keep the tie alive.
Penarol, five time winners of the Copa Libertadores, have never progressed to the Copa Sudamericana quarter-finals, let alone lifted the trophy. However, they will fancy their chances of reaching the last eight on Friday.
The Aurinegros need at least a draw to progress, which would be enough to see them extend their impressive unbeaten home record to 12 matches.
After failing to progress from the Copa Libertadores group stages, Nacional are now on the brink of exiting their second continental tournament this season, though the tie is not over yet and a one-goal deficit is within their reach.
Alejandro Capuccio knows that his side need to improve in the second leg if they are to progress, particularly in defence, after allowing Penarol to have 17 shots on their goal.
La Academia Tricolor head into Friday's game having failed to win any of their last three matches on the road, losing their most recent away game 3-0 at Torque in the Uruguayan top-flight.
Nacional need to score at last twice to advance into the last eight, something they have only done twice in their last nine away matches. They did, however, beat Penarol 2-0 in the league just under three weeks ago, so that should give them confidence heading to the Estadio Campeon del Siglo.
Penarol Copa Sudamericana form:
Penarol form (all competitions):
Nacional Copa Sudamericana form:
Nacional form (all competitions):
Team News
Penarol trio Nicolas Schiappacasse (knee), Martin Correa (muscle) and Cristian Olivera (stomach) are all ruled out with injuries.
A back four of Giovanni Gonzalez, Fabricio Formiliano, Gary Kagelmacher and Joaquin Piquerez are all set to start again in defence, shielding goalkeeper Kevin Dawson, who has kept 10 clean sheets in 19 appearances across all competitions so far this season.
Striker Agustin Alvarez, who is currently the top scorer in the Copa Sudamericana with eight goals from nine appearances, is expected to start up front and the 20-year-old will likely be supported in attack by wingers Canobbio and Facundo Torres.
As for Nacional, Capuccio may decide to make a few changes from the side that played in the first leg.
Armando Mendez is likely to come in for Mathias Laborda at right-back, while Christian Almeida could be replaced at left-back by Camilo Candido.
40-year-old Andres D'Alessandro is also set to return to the first XI at the expense of Joaquin Trasante, starting in an advance midfield role in behind 37-year-old forward Bergessio, who has scored 10 goals in as many league appearances so far this campaign.
Penarol possible starting lineup:
Dawson; Gonzalez, Formiliano, Kagelmacher, Piquerez; Gargano, Trindade; Canobbio, Ceppelini, Torres; Alvarez
Nacional possible starting lineup:
Rochet; Mendez, Marichal, Corujo, Candido; Neves, Piriz; Ocampo, D'Alessandro, Trezza; Bergessio
We say: Penarol 2-1 Nacional
Both Penarol and Nacional will fancy their chances of winning on Friday, though the pressure is on the visitors, as anything other than a win is likely to see them eliminated.
There is little to separate the two teams, but we feel that Penarol will secure another narrow victory by the same scoreline as in the first leg.