The sides have been drawn in Group E and will also take on Ivory Coast and Zambia for a place in next year's continental showpiece.
Match preview
Comoros claimed a 2-1 victory over The Walia Ibex of Ethiopia in their last involvement on March 25.
Goals from Faiz Mattoir and Abdallah Mohamed put Jimmy Abdou's men in cruise control of the contest before Surafel Dagnachew pulled one back for his side late on.
The Coelacanths have now won each of their last three home outings and are unbeaten in front of their fans since September 2019.
Awaiting them next is the challenge of an opposing outfit who claimed a first victory in this fixture in the most recent edition five years ago.
Off the back of a decent run in their first-ever AFCON tournament where they eventually bowed out to host nation Cameroon, Friday's hosts will be aiming to begin their quest for a second consecutive appearance at this level with all three points.
Lesotho played out a 1-1 stalemate against Ethiopia in Monday's meeting at the Adama Science and Technology University Stadium.
Leslie Notsi's men fell behind to Dawa Hotessa's first-half strike before drawing level through Jane Thaba-Ntso in the 71st minute.
The Crocodiles are yet to taste defeat in their four matches since the turn of the year although they only boast victory in that time.
Having won just one of their last 12 games away from home, Friday's visitors will need to geet going on the road to stand a chance of making it through to the AFCON finals.
Comoros form (all competitions):
Lesotho form (all competitions):
Team News
Lesotho have called up a largely home-based group of players with all but five of them currently plying their trades locally.
With Nkau Lerotholi missing from the latest squad, Jane Thabantso is set to close the gap in the all-time appearances charts.
Twenty-year-old Katleho Makateng opened his account for the visitors with a superb brace during the last international break and the forward is one to keep an eye on.
Youssouf M'Changama is set to record his 50th national-team cap for Comoros and would become the first player in his nation's history to reach that milestone.
Chaker Alhadhur lined up between the sticks in unfamiliar fashion during the hosts' final AFCON outing but the defender is expected to reclaim his spot in the back four this time.
Comoros possible starting lineup:
Ahamada; Youssouf, Alhadhur, M'Dahoma, Mohamed; M'Changama, Bachirou, Youssouf, Bakari; Nabouhane, M'Madi
Lesotho possible starting lineup:
Moerane; Makepe, Tseka, Mkhwanazi, Lebokollane; Bereng, Makha; Masoabi, Motebang, Thabantso; Toloane