Aguero missed a hatful of chances to become the club’s greatest ever goal-scorer, including a second half penalty.
But De Bruyne rode to the rescue with a spectacular strike on 47 minutes.
And substitute Raheem Sterling sealed the win in the final minute as City won their first two group games for the first time.
It was a moment of magic from Belgium’s De Bruyne that cast a spell over Group F rivals Shakhtar Donetsk at the Etihad.
The home side have beaten all comers so far this season but looked like meeting their match until his timely intervention put the hosts on the front foot.
Guardiola made two changes to the side that took Crystal Palace to the cleaners last weekend.
Gabriel Jesus returned to replace Sterling while Fabian Delph was given a rare start at left back in place of Benjamin Mendy, who is flying to Barcelona to see a specialist about a knee problem.
This had all pointed to a home win, not least because City came into this clash unbeaten in their last nine European outings at the Etihad, while Donetsk had never won on English soil.
It was City who dominated at the start, pinning their opponents deep into their own half and giving them no time to breathe.
Aguero threatened first, cutting inside but lashing his shot well wide before Jesus robbed Yaroslav Rakitskiy and raced clear but his cross to pick out David Silva got tangled in the Spaniard’s feet.
But once Fonseca’s men got into their stride they looked dangerous, with Fred pulling the strings in midfield.
It took a last gasp tackle from Fernandinho to stop the little Brazilian from firing his side ahead following a flowing move that ripped the home defence to bits.
City should have gone ahead themselves on 30 minutes when Jesus sent De Bruyne clean through on goal.
But with just the advancing Andriy Pyatov to beat all the midfielder could do was fire his shot wide into the side netting.
Back came Donetsk, with Marlos letting fly with a drive that had Ederson at full stretch to keep out.
Ivan Ordets should have punished City before the break when he sprung a frozen defence to latch onto a free kick, but with Ederson stranded all he could do was head wide.
Guardiola was becoming more and more agitated on the sidelines but he didn’t have to because he had De Bruyne in his side.
It was Marlos who gave the ball away in midfield and when Silva slid a pass across to De Bruyne, all it took was one glance up before he hammered a sublime strike into the top corner.
Aguero should have doubled City’s lead minutes later but volleyed straight at Pyatov from point blank range and then had his spot kick saved on a bittersweet night for the frustrated Argentine.
He was hauled off and watched Sterling show him how it’s done as he converted Bernardo Silva’s to finally see off Donetsk’s brave challenge.
