Phil Foden's first-half goal was enough to give Pep Guardiola's champions a 10th consecutive league win as they took full advantage of injury-hit Chelsea's slip-up at Stamford Bridge.
The defending champions now have 50 points after 20 matches, putting them eight clear of second-placed Chelsea. Liverpool, who lost to Leicester on Tuesday, are a further point behind.
Brentford created some good scoring opportunities in the opening stages in west London, but it was City who went ahead in the 16th minute when Foden cleverly tucked in a cross from Kevin De Bruyne.
Foden and Jack Grealish had been benched for City's wins over Newcastle and Leicester after they were pictured on a night out following the 7-0 home win over Leeds.
But the England pair were back in the starting line-up on Wednesday and Foden's goal made it a perfect 10 out of 10 for City.
The visitors dominated possession but struggled to produce shots on target and Guardiola looked edgy in the latter stages as his team attempted to see out the victory.
They thought they had sealed the three points in the dying minutes when Aymeric Laporte rose to head home but his goal was ruled out by VAR for a marginal offside.
City travel to face fourth-placed Arsenal on Saturday knowing a win would take them 11 points clear of Chelsea, who host Liverpool the following day.
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