Belgium international De Bruyne was ruled out with another knee injury this week, but that had little impact as City blew poor Saints away, Aguero taking his tally to 150 goals in 217 league appearances, while the excellent Sterling got himself a brace.
Although Saints ended City's run of six successive Premier League clean sheets with a Danny Ings penalty after half an hour, the home side were already home and dry within 18 minutes, as a Wesley Hoedt own goal was followed by Aguero and David Silva strikes.
Sterling got in on the act on the stroke of half-time and doubled his tally for the day with 23 minutes left, and Leroy Sane added a sixth in stoppage time as City emphatically returned to the Premier League summit.
Hoedt's own goal gave City a sixth-minute lead, the centre-back – whose initial failed clearance brought about the move – finding his own net when attempting to keep Sane's shot out.
Aguero doubled its tally from close range after Sterling breezed through Saints' hapless defence and passed into the danger zone.
Sterling was integral again for the third, with his cross nudged on by Sane, and Silva smashed home on the volley.
Ings' penalty – after Ederson hauled him down – saw Saints pull one back, but Sterling restored the three-goal cushion just before the interval, slotting home after tireless work from Aguero.
The visitor initially improved after the break, with James Ward-Prowse and Ings forcing Ederson into three vital saves between them.
But City still looked in control and they got a fifth just past the hour – Sterling drilling under Alex McCarthy after Aguero fed him into the area.
Sane completed the rout with a sixth in the closing minutes, picking out the bottom-left corner from the edge of the box after being found on the break by Sterling.