But City's Argentine striker Sergio Aguero missed a chance to equal the club's all-time scoring record when he had a 72nd minute penalty saved by Andriy Pyatov. The miss left him one goal behind Eric Brook's record of 177 goals in all competitions.
The Premier League leaders now top Group F on six points with Shakhtar and Napoli both on three points and look in good shape to progress to the knockout phase.
After a frustrating first half, in which Shakhtar threatened on the break thanks to some clever moves by Brazilian Bernard while City struggled to find the final pass, De Bruyne broke the deadlock.
The Belgian unleashed a fine right-foot shot from the edge of the area after being well set-up by David Silva with Shakhtar keeper Andriy Pyatov left helpless.
City should have added to their tally in the second half with Leroy Sane and Aguero both going close but it was the two substitutes who combined to make sure of the win.
Sterling, who had missed a great chance from a low De Bruyne cross made amends in the final minute when he fired home after good work from Bernardo Silva.
Guardiola said that the win had been a tricky one against a top quality opponent.
"We made an extraordinary performance, especially in the second half," he said.
"Their full-backs are amazing players, they are fast, well organised defensively. We had a lot to do to beat them. It is a big victory for us. It is a tough time always to play Shakhtar.
"It is a top team. That is why I am so satisfied. We beat one of the best teams in the way they play."
City, without injured left-back Benjamin Mendy who is heading to Barcelona to have a knee injury examined, face champions Chelsea in the Premier League on Saturday.
Shakhtar's Portuguese coach Paulo Fonseca was disappointed with the award of the penalty - when Sane went down easily as Ivan Ordets closed in and also felt his team should have had a spot-kick of their own.
But he said he was proud of the way his team had taken on the challenge at the Etihad.
"The team showed huge courage, we were very compact and didn’t leave many gaps for City and tried to attack when we had the opportunity.
"I always watch all the City matches and this year I don’t think they have played any teams that have caused them problems – so I am not happy with the loss but I am happy with my team," he said.
(Reporting by Simon Evans, editing by Pritha Sarkar)
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