The Belgian ace, who recently returned from a two-month injury lay-off after ligament damage in his right knee, walked out of the action but is naturally a concern for the boss and fans alike.
Guardiola said: "He is being checked, I don’t know right now."
De Bruyne produced a typically assured performance on the night, dictating play and producing a number of important defensive challenges to maintain City's tight grip on the game. The concern against Fulham appeared to be the player's left knee.
The Catalan boss added: "I think today Kevin is back. The Kevin we know. He made a huge effort against Shakhtar, and played few minutes in difficult conditions against Spurs.
"Today he was involved in offence and defence, hopefully what happened in the last minutes is not serious."
On the night it was young Brahim Diaz who produced his first senior goals to send City through to the quarter-finals against either Leicester or Southampton.
"Everybody was good," the manager reflected. "Brahim made two goals, Aro (Muric) - even though we didn’t concede too many chances - gave us good security.
"Phil, every time he plays at a good level. I wouldn’t single people out in particular, we made an excellent performance again - without the ball we were aggressive, we played like the competition and every game deserves.
"With the ball we were clever and we created enough chances to score more goals. I'm so satisfied with the victory."
Guardiola also spoke about how difficult it is to leave players out of his squad when there is so much quality at his disposal.
"You cannot imagine," Guardiola declared. "There are no words to explain how tough it is.
"Maybe one side of my job so easy, it’s a joy to train with these players, but at the same time so difficult."