Demyelinating diseases are commonly associated with epileptic seizures and have limited management options. Hence, the need to investigate potential options for management of such seizures. Antiaris Africana extract (AE) was investigated for effect in chronic demyelinating seizures. Cuprizone treatment induced short but frequent spike discharges in mice. Antiaris Africana extract (300 mg/kg) treatment abolished epileptiform discharges. Cuprizone administration caused severe demyelination in the corpus callosum. After the demyelination phase, myelin content decreased to 22.86 ± 1.92 % in the cuprizone-only group. However, there was an increase to 52.14 ± 3.91 % in cuprizone-only group and 62.00 ± 2.78 % in the Antiaris africana extract group respectively, after a 4-week cuprizone cessation period. Treatment with AE and LEV visibly altered myelin growth. Antiaris africana extract treatment produced significant (P < 0.001, F (3, 16) = 698.4) increase in locomotor activity similar to LEV (P < 0.001,F (2, 12) = 678.7) and DZP (P < 0.001, F (2, 12) = 620.4) and improved beam traversal time (18.71 ± 2.244 s; 95 % CI: 13.22–24.20) while causing significantly (P < 0.05, F (2, 15) = 6.667) fewer stepping errors. Antiaris africana extract inhibits seizures induced by chronic demyelination and has beneficial effects on motor coordination.