Toney, left out of England's squad for Qatar, made the most of a bright start by Brentford, breaking the deadlock in the 16th minute when Ben Mee headed back across the box and Toney sent a looping header over Ederson and into the net.
City had a strong shout for a penalty turned down for a handball before they equalised on the stroke of halftime when Kevin De Bruyne's corner was flicked on and Phil Foden drilled home a superb half-volley for his eighth league goal of the season.
City racked up goal-scoring chances in the second half but Toney fired home to round off a stoppage-time counter-attack and secure a stunning victory for Brentford.
City stayed second in the table on 32 points, two behind leaders Arsenal who play Wolverhampton Wanderers later on Saturday. Brentford are 10th on 19 points.
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