Goals by Abdellatif Noussir and Reda Hajhouj gave the North Africans a healthy advantage in the last 16 tie ahead of the return match on April 20 in Central African city Lubumbashi.
Noussir scored his first goal of the Caf campaign just before half-time and Hajhouj converted a penalty midway through the second half in Marrakech.
Coached by twice Real Madrid manager John Toshack, Wydad are attempting to win the competition a second time, having previously succeeded in 1992.
Mazembe are chasing a sixth title, which would make them the second most successful club after eight-time champions Al Ahly of Egypt.
Wydad or Mazembe and seven other last 16 winners advance to the lucrative group phase, while the losers drop to play-offs in the second-tier Caf Confederation Cup.
Ahly are set to end a run of two successive failures to make the mini-leagues after holding Young Africans of Tanzania 1-1 in Dar es Salaam.
Amr Gamal nodded the Cairo Red Devils ahead after 11 minutes only for former Fiorentina defender Ahmed Hegazy to concede an own goal soon after.
Ahly are guided by former Tottenham Hotspur and Fulham manager Martin Jol, who signed an 18-month contract in February.
Another ex-English Premier League boss, Alex McLeish, maintained a 100 percent Caf record as Zamalek of Egypt defeated Mouloudia Bejaia of Algeria 2-0 in Cairo.
Scot McLeish, who managed Birmingham City and neighbours Aston Villa, saw Mahmoud ‘Kahraba’ Abdel Moneim put the White Knights ahead just before the hour.
Zamalek, who won the last of five Champions League titles 14 years ago, doubled the lead eight minutes from time via Ahmed Hamoudi.
Stade Malien had hopes of becoming the first qualifiers from Mali all but dashed after a shock 3-1 home loss to Zesco United of Zambia.
The game began promisingly for the hosts as Moussakoye Diallo scored, but Mwape Mwelwa levelled before half-time and Idris Ilunga bagged a late brace.
Asec Mimosas broke a two-match Caf goal drought at home by beating Al Ahly Tripoli 2-0 in Abidjan thanks to second half goals from Youssouf Dao and Serge Arnaud Aka.
Twice champions Entente Setif of Algeria led twice in a 2-2 draw away to 2015 semi-finalists Al Merrikh of Sudan in Omdurman.
Eudes Dagoulou and Abdelmoumen Djabou scored for Setif and Rajib Abdelatti got both equalisers.
Two first legs are scheduled for Sunday with V Club of DR Congo hosting Mamelodi Sundowns of South Africa and Enyimba of Nigeria at home to Etoile Sahel of Tunisia.
