The match marked the return of Aguero to Pep Guardiola's starting lineup for just the fifth time across all competitions this season, with the Argentine dealing with injuries for much of the season and having not scored in the league since a Jan. 21, 2020 goal against Sheffield United.
Despite looking like the inferior side on paper and in the table, the hosts, who have kept clean sheets in five of their last nine matches, kept Man City off the scoresheet in the first half and went to the break still on level terms.
John Stones put Man City in front just after half-time, redirecting a whipped in free kick from Joao Cancelo with a fine first-time shot to make it 1-0.
Gabriel Jesus doubled the lead for the Premier League leaders 10 minutes later when he picked up a deflected clearance, rounded Fulham keeper Alphonse Areola and buried a shot into the back of the net.
Aguero then scored from the penalty spot, sending his kick just wide of a diving Areola and putting the result well out of reach for Fulham.
The result leaves Man City on 71 points from 30 matches, miles ahead of second-placed Man United, while Fulham remain firmly in a relegation battle in 18th place on 26 points.
Home manager Scott Parker would have been delighted with the way his team managed City in the first half, restricting Guardiola's side to half chances.
But they self-destructed in the second half, culpable in all three of City goals.
"We tried to take the game to the best team in Europe and this division. I thought we did do that. We conceded silly goals in the second half," Parker said.
"I asked the team to be brave and show a way about us to try and assert ourselves on Man City. For large parts they did very well but it was some silly goals, really."