Epidemiological studies support the idea that multiple sclerosis (MS) is a multifactorial disease, overlapping genetic, epigenetic, and environmental factors. A better definition of environmental risks is critical to understand both etiology and the sex-related differences of MS. Exposure to endocrine-disrupting compounds (EDCs) fully represents one of these risks. EDCs are natural or synthetic exogenous substances (or mixtures) that alter the functions of the endocrine system. Among synthetic EDCs, exposure to bisphenol A (BPA) has been implicated in the etiology of MS, but to date, controversial data has emerged. Furthermore, nothing is known about bisphenol S (BPS), one of the most widely used substitutes for BPA. As exposure to bisphenols will not disappear soon, it is necessary to clarify their role also in this pathological condition defining their role in disease onset and course in both sexes. In this study, we examined, in both sexes, the effects of perinatal exposure to BPA and BPS in one of the most widely used mouse models of MS, experimental autoimmune encephalomyelitis (EAE). Exposure to bisphenols seemed to be particularly deleterious in males. In fact, both BPA- and BPS-treated males showed anticipation of the disease onset and an increased motoneuron loss in the spinal cord. Overall, BPA-treated males also displayed an exacerbation of EAE course and an increase in inflammation markers in the spinal cord. Analyzing the consequences of bisphenol exposure on EAE will help to better understand the role of both xenoestrogens and endogenous estrogens on the sexually dimorphic characteristics of MS.