While Wydad won four and drew three of eight matches en route to the knockout phase, Setif scraped into the last eight after four victories, three draws and three losses.
Both sides have won the elite African club competition twice — Wydad in 1992 and last year and Setif in 1988 and 2014.
Record eight-time champions Al Ahly of Egypt, beaten by Wydad in the 2017 final, must defeat Horoya of Guinea to set up a possible rematch with the Moroccans at the semi-final stage.
Horoya were surprise qualifiers from Group C at the expense of 2016 champions Mamelodi Sundowns of South Africa.
Wydad and Ahly should progress and many pundits are sure to label a last-four clash between the north Africans giants “the final before the final”.
TP Mazembe of the Democratic Republic of Congo appear the strongest side in the other half of the draw and it would be a shock if they failed to eliminate Primeiro Agosto of Angola.
The Congolese outfit from southern city Lubumbashi have won the competition five times, most recently in 2015, while Primeiro are last-eight debutants.
Esperance will enjoy home advantage first against Etoile Sahel in an all-Tunisia affair that appears the most intriguing of the quarter-finals.
Among the survivors, only Esperance have avoided losing away this season en route to the knockout stage, winning one match, drawing four and conceding only one goal.
Based in Mediterranean resort Sousse, Etoile are the only side to have won all five current and past CAF club competitions.
They caused a sensation in 2007 by defeating seemingly invincible Ahly 3-1 away in the second leg of the Champions League final after being held at home.
Amine Chermiti, a survivor from that team, scored four of the 14 goals that took Etoile to the quarter-finals this season.
Primeiro Agosto (ANG) v TP Mazembe (COD)
Esperance (TUN) v Etoile Sahel (TUN)
Entente Setif (ALG) v Wydad Casablanca (MAR, holders)
Horoya (GUI) v Al Ahly (EGY)
First legs: Sept 14/15, second: Sept 21/22
Horoya or Ahly v Setif or Wydad
Primeiro or Mazembe v Esperance or Etoile
First legs: Oct 2, second: Oct 23
Horoya, Ahly, Setif or Wydad v Primeiro, Mazembe, Esperance or Etoile
First leg: Nov 2, second: Nov 9
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