The Algerians scored once in each half at the Stade Chedly-Zouiten to pull four points clear atop Group B.
El Hedi Belameiri and Sofiane Younes were on the scoresheet against the Libyan hosts, who stayed third in the group.
The visitors needed 18 minutes to open the scoring, and it was Younes who set up Belameiri to make it 1-0.
Jozef Vukusic's men were in the contest throughout, but their chances of taking anything out of the game were ended in second-half additional time.
Younes went from provider to scorer, sealing the three points as ES Setif took a huge step towards the last four.
The group's two other teams – CS Sfaxien and ES Tunis – meet on Saturday before the final two matchdays.