Pepe earned the Great Danes a crucial win in their quest for an automatic return to Uefa Champions League with his 17th league goal of the season.
The 23-year-old was played through by Luiz Araujo before cutting inside Saint-Etienne's defence to separate both teams with his effort in the 87th minute.
Few minutes later, the hosts were dealt a massive blow after Mathieu Debuchy and Wahbi Khazri were sent off late on.
Debuchy was shown a second yellow card in the 90th minute and Khazri was shown a straight red card for a challenge on Loic Remy in the stoppage time.
The victory moved Lille seven points clear in the second spot with 57 points from 28 matches while the Greens dropped to sixth in the Ligue 1 log.