Karl Toko Ekambi gave the Indomitable Lions lead just before the half hour mark with a neat finish inside the area.
Captain Vincent Aboubakar doubled their advantage 20 minutes from time before Comoros captain Youssouf M'Changama pulled a goal back from free kick.
Defender Chaker Alhadhur started in goal for Comoros who were without their recognised goalkeepers for the last 16 match at the Stade Olembe in Yaoundé.
The debutants had a difficult start against Cameroon when captain Nadjim Abdou was sent off after 7 minutes for a foul on Moumi Ngamaleu.
With a man down Comoros put up brave performance against the Indomitable Lions. Andre Onana had to be at his best to keep Cameroon in the match, the Ajax goalkeeper pulled the first save of the match inside two minutes.
Onana parried away Youssouf M'Changama free kick before Collins Fai cleared the rebound.
Aboubakar was presented a great chance to increase his tournament tally, when Ekambi found him in space but his effort went wide.
Ekambi scored from a Aboubakar's pass to ease the pressure on the home faithful with a well taken strike.
Onana denied Comoros with a double save to keep Cameroon's lead on 32 minutes. Ahmed Mogni fired a low goal bound strike which Onana turned away before blocking Mohamed Baki's follow up strike.
The second half was more open with both side creating chances while both goalkeepers pulled brilliant saves.
Chaker Alhadhur denied Aboubakar seven minutes after the restart with a great save.
Aboubakar found the back of the net but he was flagged offside on 64 minutes as Cameroon search for the winner.
The tournament's leading scorer got his goal on 70 minutes to become the first player in the 21st century to score more than 5 goals in a single TotalEnergies Africa Cup of Nations finals.
Comoros pulled a goal back from Youssouf M'Changama's long range free kick to set up for a thrilling end.
Onana had earlier saved Abdallah Ali Mohamed and El Fardou Ben Mohamed to send the hosts through.
The Indomitable Lions will face The Gambia who beat Guinea to progress to the quarter finals.