Head coach Fernando Santos described Pepe as a “monster” ahead of the Group H clash and the former Real Madrid centre-back is set for an intriguing head-to-head battle with Uruguay’s star-studded forward line.
Portugal are expected to be without Danilo Pereira for the rest of the World Cup after the Paris Saint-Germain defender fractured his ribs in training this week.
That has opened the door for Pepe, who at 39 years and 275 days will become the oldest player to play in a World Cup game for Portugal.
“He is a monster,” said Santos. “He’s going to play.”
Cristiano Ronaldo will captain Portugal amid reports he has been offered a three-year contract with Saudi Arabian club Al Nassr worth more than £180million which would see him become the highest-paid player in football history.
Uruguay are again set to be without Barcelona centre-back Ronald Araujo, who underwent thigh surgery in September.
Starting Portugal XI: Diogo Costa; Cancelo, Dias, Pepe, Mendes; Neves, Carvalho; Silva, Fernandes, Félix; Ronaldo.
Starting Uruguay XI: Rochet; Gimenez, Godin, Coates; Varela, Valverde, Bentancur, Vecino, Olivera; Cavani, Nunez