Mothiba kept his spot in the side after bagging a goal and an assist last weekend as he jined Ludovic Ajorque in the attack. Lyon, meanwhile, were without talisman Memphis Depya through injury.
It was the home side who drew first blood as Ajorque turned provider to pick out Youssuof Fofana, who fired home his first goal of the season.
After a slow period in the second half, Lyon managed to restore parity five minutes before the halftime break courtesy of a strike from Maxwell Cornet.
Lyon were eager to get back on the winning trail following defeat to Zenit St Petersburg in the UEFA Champions League on Wednesday evening.
That drive and eagernes resulted in a second goal with 15 minutes remaining, with former Arsenal starlet Jeff Reine-Adelaide.
Strasbourg were unable to find way a back in the contest, while Mothiba lasted 89 minutes before he was replaced by Ivorian Kevin Zohi as Lyon held on for the win.