Fatih Terim's men headed into Sunday’s big game with a poor record of a win in their past 15 attempts in Istanbul derbies.
With title rivals Istanbul Basaksehir having dropped points against Sivasspor in Friday's encounter, the win places the title race in Galatasaray's hands.
They got the opener through Onyekuru moments before the first-half break. Fernando wrapped up the vital victory for the defending champions in the 54th minute.
The win saw them move to the top of the table with 63 points after 31 games, same as Basaksehir who are eight goals  adrift of the new log leaders.
The Everton loanee, Onyekuru has scored 13 goals in 28 Turkish top-flight games so far this season.
The Super Eagles are drawn in Group B alongside Burundi, Guinea and Madagascar.