The South African striker was named in the Lille starting line-up for the third successive game this season, looking to add to his one goal.
It was meant to be a clash of the South Africans but Lebogang Phiri missed out for Guingamp through injury.
Seven minutes into the clash, Lille broke the deadlock with Xeka opening the scoring after being teed up Pepe.
Jonathan Bamba doubled the lead four minutes later with his first of the campaign.
Bamba put the incing on the cake with his second of the game after 73 minutes, with Pepe registering another assist.
Mothiba, who last scored on the opening day, only featured for 75 minutes before being replaced by Loic Remy.
Lille will now turn their attention to next week's away trip to Angers.