Degenerative cervical myelopathy (DCM) is a severe condition of the spinal cord caused by chronic compression. However, no studies to date have examined the effects of zonisamide (ZNS) on DCM via the Fas/FasL-mediated pathway. The aim of this study was to investigate the effects of ZNS on a DCM rat model and to explore the potential mechanisms. First, 40 adult Sprague-Dawley rats were used to establish the DCM rat model and were individually divided into four groups: the Sham group, DCM model group (DCM), ZNS group (DCM model rats treated with ZNS, 30 mg/kg/day), and ZNS + CD95 group (DCM model rats treated with ZNS and CD95). Histopathology injury and cell apoptosis, Fas and Fas ligand (FasL) expression and Fas/FasL relative protein levels were detected by hematoxylin and eosin staining, TUNEL assay, and immunofluorescence and western blotting, respectively. The results of our study demonstrated that ZNS could promote motor recovery while reversing histopathological injury and cell apoptosis in DCM rats. Moreover, Iba-1, Fas and FasL expression in DCM rats was decreased, accompanied by a decrease in cleaved caspase-3/caspase-3, cleaved caspase-8/caspase-8, cleaved caspase-9/caspase-9, cleaved caspase-10/caspase-10 and B-cell lymphoma-2 (Bcl-2)/Bcl-2 associated X (Bax) levels. All these results revealed that ZNS attenuates DCM injury in a rat model via the regulation of Fas and FasL signaling. Our study indicated that ZNS had beneficial effects on DCM and thus provided a novel theoretical approach for subsequent academic and clinical research on DCM injury.