The Manchester City full-back missed Saturday's 4-0 win against the Czech Republic, where Diogo Dalot deputised extremely well, scoring two of his side's goals on the night.
Fernando Santos should therefore be reluctant to drop Dalot from the side, although Cancelo is perfectly capable of operating on either side of the backline, so a left-back role may be calling for him.
Mario Rui and Nuno Mendes would therefore be forced to accept spots on the bench, while Danilo Pereira and Ruben Dias should pair up at the back following Pepe's withdrawal.
Diogo Costa was given the nod in goal over Rui Patricio on matchday five and has no reason to lose his place after keeping a clean sheet, but there could be an alteration in the engine room.
Ruben Neves and Bruno Fernandes are seemingly set to hold their spots, but William Carvalho's place is under threat as Fulham's star man Joao Palhinha pushes for inclusion.
Cristiano Ronaldo was left bloodied following a clash with Tomas Vaclik last time out, but the 37-year-old was able to carry on and set up Diogo Jota's late goal and will seemingly be fine to start here.
Jota will threaten to force his way into the attack, but Bernardo Silva and Rafael Leao should support Ronaldo from the off once again as Portugal aim to qualify for the finals with a win or draw.
Portugal possible starting lineup: Costa; Dalot, Dias, Pereira, Cancelo; Neves, Palhinha, Fernandes; B. Silva, Ronaldo, Leao