Mothiba was left out of the Strasbourg squad while former Orlando Pirates defender Marshall Munetsi started on the bench for Reims.
Ludovic Ajorque almost rewarded his side on 11 minutes following a shot with his outside left after winning possession high up the pitch, but failed to find the target.
Reims quickly regained confidence following the slow start, as Hassane Kamara and Bingourou Kamara put the visitors in a spot of bother either end of the pitch following the half-hour mark.
The danger wasn't over for the visitors following the second half, as Kamara was forced to dive to his right to parry Remi Oudin's powerful strike on goal 48 minutes gone.
Strasbourg responded though with a big chance of their own three minutes later after Youssouf Fofana surged on to a cross from the left to bring the best out of Predrag Rajkovic.
Just a minute later, the home side refreshed their system with the introduction of Nathanael Mbuku who came on for Mathieu Cafaro.
Mbuku's time on the field ended as quickly as he set foot, as he received a straight red card four minutes later following a foul on Adrien Thomasson.
The visitors looked to make use of the man advantage later on, but despite the introduction of Kevin Zohi to their attack couldn't find the all important breakthrough.
The game eventually went to a penalty shoot-out, where Yunis Abdelhamid fired the winning kick after the visitors missed two to guide Reims into the semi-finals.