Fernando Santos accepted Ronaldo's request to be rested and, while there may have been some pre-match trepidation about the team's chances without the Juventus star, Portugal went on to dominate Italy in Lisbon.
Roberto Mancini's men rode their luck in the first half, relying on a goal-line clearance from Andrea Romagnoli and the frame of the goal to keep them on level terms.
But Portugal found a way through just after the break – lively Sevilla striker Andre Silva producing a neat finish after a devastating Bruma-inspired counter - and that proved to be winning goal.
Italy looked every inch a team which featured nine alterations from its last outing, as Portugal looked the more coherent and carved them open in the 14th minute, only for Bernardo Silva to play a poor pass into the danger zone instead of shooting.
Romagnoli then had to be alert just before the half-hour mark, clearing Bernardo Silva's effort off the line after Andre Silva made a nuisance of himself.
Italy were fortunate again a few moments later – Mario Rui's low cross deflecting off Bryan Cristante and coming back off the crossbar.
Portugal's persistence finally paid off three minutes into the second half, with Andre Silva curling into the bottom corner after Bruma's low cross was deflected into his path.
Bernardo Silva tested Gianluigi Donnarumma with a stinging drive soon after, one of few second-half opportunities, despite Portugal's dominance.
Yet, Italy rarely threatened to restore parity and Portugal secured a deserved victory.