In ugly scenes at the DW Stadium, Wigan fans charged onto the pitch at full time with some taunting the Premier League leaders.
Aguero appeared to try and shake off a mocking fan after an altercation.
And he had to be dragged away after trying to get at the supporter a second time.
BBC pundit Alan Shearer said of the incident: “You don’t know what he’s done to Sergio or what he’s said to him.
“It’s not nice when the fans come on the pitch and say stuff to you so let’s hope everyone is okay.”
Sergio Aguero appears to strike out at a Wigan fan
The moment Sergio Aguero hits out
The man in the green jacket can be seen falling backwards following Aguero’s reaction.
Argentine Aguero had started the match with Wigan but was unable to prevent Manchester City falling to a 1-0 defeat.
Fabian Delph was sent off in first-half added time for a lunging challenge on Max Power.
That sparked an incident in the Wigan tunnel, where Pep Guardiola and Paul Cook had to be separated by coach Peter Reid.
The hosts eventually took advantage of the extra man when Will Grigg scored the winning goal on the 79th minute to dump City out of the FA Cup.
The victory sparked wild celebrations by Latics supporters and they invaded the pitch on the final whistle.
Man City ironically posted a “fighting” message on Twitter.
As one Wigan fan ran towards him Aguero acted in self defence by swinging his arm and striking the man in the face.
Ironically, moments after the incident, Manchester City tweeted a photo of their dejected players with the caption “we’ll keep on fighting.”
However, Guardiola played down the clash when asked about the incident.
Asked about the tunnel incident after the game, Guardiola said: “Nothing happened.”
And he was equally as curt about the sending off: “Red card. It was the decision.
“Congratulations for Wigan for the qualification.
Aguero (centre) has to be restrained by one of his team-mates.
Wigan fans invaded the pitch on the final whistle.
“We did absolutely everything, we made a mistake and this kind of game is like a final. OK, we accept the defeat.
“Congratulations to the winner.”
League One outfit Wigan completely upset to odds to bring City’s quadruple hopes crashing down.
And Wigan boss Cook was delighted with the win.
He said: “It was such a severe test, in everything. They are such a good side, they move the ball so well.
“Tonight we had to ride our luck at times, the sending off is always a big incident in the game.
“We had to ride our luck with a couple of flashing crosses, but that’s what makes the FA Cup so special.
“Our lads deserve a lot of credit for the amount of work and the level of energy they put in. To beat a Man City team you have to do that.”