The Comoros started with left-back Chaker Alhadhur between the posts in Yaounde after two of their three goalkeepers were ruled out due to Covid-19 while the other was missing due to injury.
They then had captain Nadjim Abdou sent off after just seven minutes, and Karl Toko-Ekambi put Cameroon in front before skipper Vincent Aboubakar netted his sixth goal of the tournament.
Despite that it was a heroic performance from the Comoros, who kept the tie alive until the end thanks to Youssouf M'Changama's stunning late free-kick.
The Indomitable Lions keep their dream of winning the Cup of Nations on home soil alive as they advance to a last-eight tie against Gambia on Saturday, yet this was the Comoros' night, despite the outcome.
The tiny Indian Ocean island nation qualified for the last 16 in their first ever appearance at the Cup of Nations after finishing as one of the best third-placed teams in the group stage.
However, their dream turned to a nightmare as a total of 12 players and staff tested positive for Covid-19 two days before the tie, including goalkeepers Ali Ahamada and Moyadh Ousseini.
Their other goalkeeper, Salim Ben Boina, was injured but they had hoped Ahamada would be able to start after he tested negative on the day of the game.
The 30-year-old Ahamada flew from Garoua, where he had been isolating, to Yaounde on Monday afternoon in the hope of being able to play, only for the Confederation of African Football (CAF) to decide otherwise as his positive result had come just two days earlier.
Alhadhur, a reserve left-back for French Ligue 2 side Ajaccio, wore the gloves, with tape used to mark out his number three on the back of his goalkeeper's jersey.
It was a farcical scene, and the Comoros' plight worsened when Abdou was shown a straight red card for a foul on Moumi Ngamaleu after the Ethiopian referee went to review images of his challenge.
Rather than give up, the Comoros kept going and they only fell behind in the 29th minute when Aboubakar teed up Toko-Ekambi to slot home.
The islanders, whose coach Amir Abdou was among those missing after testing positive, almost equalised shortly after as Ahmed Mogni forced Cameroon goalkeeper Andre Onana into a fine save.
Aboubakar had a second-half effort disallowed for offside before making it 2-0 with 20 minutes left, finishing excellently after being picked out by Martin Hongla.
Yet there was no collapse from the Comoros, who pulled one back courtesy of M'Changama's piledriver from 35 metres and go out with their heads held high.
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