Ulinastatin has previously been used as a drug for patients with acute inflammatory disorders. The goal of the present study was to investigate the protective effects of ulinastatin on myelin sheaths and oligodendrocytes in experimental autoimmune encephalomyelitis (EAE), and to explore the possible underlying mechanism. Mice were divided into an ulinastatin treatment group, a normal saline treatment group, and a normal control group. EAE was induced in the mice with and without ulinastatin treatment. Demyelination was evaluated, as was the number of oligodendrocytes. The ulinastatin treatment group had a significantly lower clinical score, demyelinating score, and large numbers of oligodendrocytes compared with the group without ulinastatin treatment. Furthermore, ulinastatin treatment increased the expression of nerve growth factor and brain-derived neurotrophic factor, and protected against oligodendrocyte apoptosis. Thus, ulinastatin is shown to have a protective effect against EAE.