Pep Guardiola believes some Manchester City players will feel he makes "unfair" decisions if they are left out of the team.
Both players came off the bench in the second half with De Bruyne's whipped cross deflecting in off Wolves captain Conor Coady, but Aguero had to watch his replacement Gabriel Jesus score a first-half brace.
City are still competing in four competitions and Guardiola accepts he has to make difficult decisions over his team selection on a game-by-game basis.
"I have an incredible squad, so if Kevin plays like he deserves to play, maybe [Ilkay] Gundogan doesn't play - he made maybe six or seven assists in the last two games. He didn't play today - and both deserve to play," Guardiola told a news conference.
"But Bernardo [Silva] also deserves to play, what he has done so far, and Fernandinho what he has done against Liverpool. So that's where he is and we've spoken about that. Today one of my favourite players, Phil [Foden], he was in the tribune.
"But there is a lot of games and everybody is going to play. Maybe the next game, new players are going to come in. So they have to be ready, and not only that they have to play good in all the details. Because if they don't, another one is going to play.
"After that I make a mistake, of course, I am unfair for many, many players and I know that. But today I decided for that and for the fresh players - like Aymeric [Laporte], John [Stones], Bernardo, Fernandinho - so it is what it is."
Aguero's illness has allowed Jesus to stake his claim with a remarkable run of seven goals in his last three City appearances.
But Guardiola will not be losing any sleep over deciding which of the two strikers deserves to start City's next game, away to Huddersfield Town in the Premier League on Sunday.
"I'm a courage manager," he said. "I will dream, I will sleep, I will talk to my staff and I will see what happens. And I will try to involve everybody.
"We spoke the last games that were amazing, Southampton and Liverpool and two in the cups. Everybody played, everybody, so everybody is a part of that. And in the next game, everybody is going to be part of it.
"So, when we play four competitions, I don't like to just play 11 or 12 players. It's impossible to sustain it, not just for the physicality but for the players and for the locker room. Everybody has to be ready.
"Some players play more than the other ones, always this happens, but still we are in four competitions and everybody is going to play until the end of the season."