Second-half strikes from Michelle Alozie and Uchenna Kanu propelled the Super Falcons past the Coelacanths at the Remo Stars Stadium.
Although Comoros were the hosts, they were made to play in Ikenne-Remo because they do not have a stadium that meets the requirements set by the Confederation of African Football.
Nigeria entered the contest as overwhelming favourites against a Comoros side that had obliterated Sudan 30-0 on aggregate in the first round.
The 10-time African champions dominated proceedings from the opening minutes but struggled to convert their chances.
In the 11th minute, a well-worked attacking move created an opportunity for Toni Payne, whose curling effort went wide.
Nigeria went even closer in the 26th minute when Payne set up captain Rasheedat Ajibade, but her effort struck the crossbar before Glory Ogbonna failed to convert the rebound.
Despite creating several opportunities, the Super Falcons went into the half-time break with the scoreline still goalless.
However, the breakthrough arrived three minutes after the restart when Gift Monday headed a cross into Alozie's path, allowing the defender to finish calmly from close range.
They doubled their advantage two minutes after the hour mark when Kanu headed home a corner delivered by Jennifer Echegini.
Comoros struggled to create meaningful chances as Nigeria maintained control and comfortably protected their two-goal advantage until the final whistle.
The result puts the Super Falcons in a strong position ahead of Tuesday's return leg, which will also take place in Ikenne.
The aggregate winners will advance to the third round of the five-stage African qualifying series, where Morocco await following the withdrawal of the Republic of Congo.
