The Black Stars needed to win to advance from Group C, but after a late rally, they were defeated for the second time in the competition at the Roumde Adjia Stadium.
El Fardou Ben Mohamed created history for Comoros after just four minutes, scoring his country's first ever AFCON goal.
After 25 minutes, Ghana's problems were exacerbated when captain Andre Ayew was issued a straight red card.
Following a VAR review, Ayew was sent off after diving in after a loose ball on Comoros goalkeeper Salim Ben Boina.
With half an hour to go, Ahmed Mogni's spectacular solo effort increased the advantage for Comoros, who appeared to be in complete control.
Despite being down to ten men, Partey's team produced some of their finest football of the tournament, scoring twice in the final eight minutes to tie the game.
To begin, Richmond Boakye ran from a corner to offer Ghana hope. Partey then passed to Alexander Djiku in the box, who bundled home with 13 minutes remaining.
Ghana's dreams of a dramatic triumph were shortly dashed when Mongi scored his second goal of the game in the 85th minute, turning the ball home from close range to secure a famous victory for the Comoros.
AFCON 2021: Partey's Ghana knocked out by Comoros | News | Arsenal.com" https://www.arsenal.com/news/afcon-2021-parteys-ghana-knocked-out-comoros
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