Goalkeeper Ederson Moraes, Aymeric Laporte, Ruben Dias, Rodri, Bernardo Silva and Raheem Sterling were recalled to the City side after their victory over Fulham on Saturday.
Despite the even start, the Bees orchestrated the game's first chance at the midway point through a clever effort in the area from Mathias Jensen from a pass by Ethan Pinnock.
City started to pull together shortly before the half-hour mark and required goalkeeper David Raya to parry Riyad Mahrez's teasing cross before Joao Cancelo hoofed the follow-up.
The Citizens, who continued to see openings five minutes to halftime, received a breakthrough when Sterling drew a foul from Mads Rasmussen to win a penalty which Mahrez tucked away.
Brentford looked for a different start to the second period, but still struggled to penetrate the Citizens who closed in on a second through Cancelo after he cut into the area.
Pep Guardiola put on a substitution midway in the second half as Jack Grealish replaced goal-scorer Mahrez as the match remained a tightly knit at this point in time.
However, the Citizens made their advantage all more comfortable within a few seconds after Kevin De Bruyne latched onto a loose pass outside the area to slot into an unguarded net.
Brentford's Raya was worked overtime in the last ten minutes as Rodri closed in with a first-time strike on the edge of the area which the self-same Raya staved off.
The defending champions had no problems holding the visitors at bay following the latter minutes and went on to snatch a narrow victory.