Both teams are away next weekend, with PSG at Brest and Lille facing Angers.
PSG coasted after Reims had defender Yunis Abdelhamid sent off in the 11th minute for a handball, and Neymar converted the penalty with a staggered run-up followed by a typically casual shot which sent the goalkeeper the wrong way.
Kylian Mbappe doubled the lead midway through the first half after a mistake from defender Thomas Foket, who sent the ball in his own penalty area straight to Mbappe for a league-leading 26th goal and 40th overall this season.
Central defender Marquinhos scored with a trademark downward header midway through the second half and Italy striker Moise Kean completed the scoring in the last minute.
Lille struggled to break down an organized Saint-Etienne side but came close to scoring in the 36th when Luiz Araujo's shot sailed just wide after he latched onto striker Burak Yilmaz's astute pass.
Lille almost won during injury time but attacking midfielder Yusuf Yazici's free kick hit the post and Yilmaz's shot from the rebound was blocked by a defender.
Additional reporting by AP.