The Ghanaians needed an outright win to boost their chances of qualification to the next stage only to be reduced to 10 men in the 25th minute.
Captain Andre Ayew was sent off and Comoros capitalized on their numerical advantage to go two goals up.
Ghana would fight for their continuation in the competition to level the scores at 2-2 but Comoros scored a late winner to send the Black Stars out.
After the game, Nigerians took to Twitter to celebrate the elimination of west African rivals Ghana.
Key to the celebration was Ghanaian reggae-dancehall artiste Charles Nii Armah Mensah Jr whose stage name is Shatta Wale.
Shatta Wale faced the full brunt of criticism for his country's exit from the tournament.
Shatta Wale stated recently that Nigerian artists do not promote their Ghanian counterparts.
This assertion by Shatta Wale resulted in retaliation by Nigerian fans on Twitter after Ghana exited the AFCON.
While Ghana exited the tournament, Nigeria's Super Eagles take on Guinea Bissau in their last group game scheduled for Wednesday, January 19, 2022, with qualification to the knockout stages already secure.