De Bruyne only came off the bench in the 89th minute at Tottenham Hotspur Stadium and was unable to inspire a late comeback as City fell to a 1-0 defeat in the first leg of their Champions League quarter-final.
Guardiola chose Ilkay Gundogan and Fernandinho to support David Silva in midfield, but City did not manage a shot on target after the 47th minute, meaning Son Heung-min's 78th-minute strike proved decisive after Sergio Aguero missed a first-half penalty.
City boss Guardiola insists his side played well, though, having explained he left out De Bruyne to make the core of his side more defensively sound.
"I decided to play with two holding midfielders in that position to be a bit more solid," he told a news conference. "I decided for the other ones. I know it is tough for him [De Bruyne]."
He said of the result: "Now we know what we have to do. I have the feeling the game was quite good. We controlled them and arrived with some quality situations.
"In the high competitions, at a high level, you have to live these situations. Now we have another option, another chance and that is the point.
"They had a few chances on the counter-attack but we controlled the game and played quite good.
PEP Except for a few chances at set pieces and some counter-attacks, we controlled the game. We are going to try at home, with our fans, with our families.— Manchester City (@ManCity) April 9, 2019
The situation is what it is. When we are not good I say so but I don’t have that feeling.
#thfcvcity #mancity pic.twitter.com/YEiJiQHQt1
"If we are not able to arrive in the last stages [of the tournament] it is because it is a challenge. The situation is what it is.
"When we don't play good, I am the guy who says we didn't play good, but I don't have that feeling."
Bernardo Silva was also omitted, having picked up a problem in training, but Guardiola hopes to have him back for next week's second leg.
"In the season there are injuries, there are problems and I hope Bernardo will be fit in the next week," he said.
Guardiola has now called on City fans to make the return at the Etihad Stadium a daunting prospect for Spurs, as he attempts to keep his own side's quadruple challenge on track.
"We did not have a single day to prepare training on the pitch; they had six days," he said.
"Hopefully, our people can support us every single minute. Hopefully, the Etihad is full
"We know what we have to do: score goals, play as best as possible. We are going to try."