The Manchester City midfielder's involvement in the Euros was delayed due to facial fractures sustained in the Champions League final.
De Bruyne had subsequently starred as Belgium eased through the group stage, however, assisting one and scoring another in a comeback win over Denmark, before laying on a further assist against Finland.
But he lasted just 48 minutes of the knockout game against Portugal in Seville.
Joao Palhinha had been booked just before half-time for a challenge on De Bruyne from behind, and the felled star soon found he could not continue in the second period.
Red Devils coach Roberto Martinez took no risk, quickly calling Dries Mertens on in De Bruyne's place.
Belgium would have to face in-form Italy if they advance, while world champions France are also in the same half of the draw – two opponents against whom they would not like to be without De Bruyne.