Cellular stress can lead to the production of reactive oxygen species (ROS) while autophagy, as a catabolic pathway, protects the cells against stress. Autophagy in its turn plays a pivotal role in the pathophysiology of multiple sclerosis (MS). In the current review, we first summarized the contribution of ROS and autophagy to MS pathogenesis. Then probable crosstalk between these two pathways through HIF-1α for the first time has been proposed with the hope of employing a better understanding of MS pathophysiology and probable therapeutic approaches.