The South American side will take on European opposition in Montevideo prior to matches with England and Italy in Group D in Brazil.
All the talk in Uruguay's camp has been over Liverpool striker Luis Suarez's fitness but the team must now turn its attention to facing Northern Ireland.
The 27-year-old was injured in training last week and underwent surgery after it was revealed he had suffered meniscus damage in his left knee.
Suarez's injury has raised questions over whether he will be fit for the upcoming World Cup in Brazil.
The former Ajax man is confident he will play his part on the biggest stage of all in football, but he will not feature in Saturday's friendly at the Centenario in Montevideo.
If the former Ajax man is ruled out of the tournament, then Edinson Cavani will be under more pressure to provide a goal threat.
The Paris Saint-Germain frontman is hopeful that his fellow striker, who scored 11 goals in qualification, will win his fitness battle, though.
Cavani told El Pais: "We're all a bit discouraged by what happened. Injuries are always ugly and more so at this time.
"I think we have to leave him alone now so he can have a good recovery with no anxiety on him. We wish he can join us as soon as possible."
Record cap-holder Diego Forlan could lead the line in the absence of Suarez this weekend.
Uruguay needed to come through an intercontinental playoff against Jordan to seal a place in the finals in Brazil.
The team then drew 1-1 with Austria in March and coach Oscar Tabarez will see a home friendly against Northern Ireland as an opportunity to get into stride ahead of the team's World Cup Group D opener against Costa Rica on June 14.
Northern Ireland boss Michael O'Neill, meanwhile, has named five uncapped players in his squad: Trevor Carson, Ryan McLaughlin, Luke McCullough, Paul Paton and Liam Donnelly.
Manchester United defender Jonny Evans, West Brom duo Gareth McAuley and Chris Brunt, Palermo forward Kyle Lafferty and Hull City's Alex Bruce are among the absentees along with Derby County's Jamie Ward.
Northern Ireland secured a shock win against Russia in its World Cup qualifying group, but that was the only victory in 10 attempts as the team finished second from bottom.