The Coelacanths secured all three points at home, positioning themselves at the top of Group I after triumphing over the Central African Republic in their opening game.
However, Myziane Maolida's solo run and subsequent goal in the 43rd minute provided Comoros with a crucial advantage heading into halftime.
Attempts from Semenyo, Inaki Williams, and substitute Majeed Ashimeru were unsuccessful in equalizing the score.
Inaki Williams had a late opportunity from an Abdul Fatawu Issahaku cross, but his header failed to trouble the goalkeeper.
Despite a late effort to secure an equalizer, the Black Stars could not overcome Comoros, resulting in a defeat.
The victory propels Comoros to the top of Group I with two wins in two games, while Ghana remains on three points.