Background: This study explored the efficacy of kolaviron—a biflavonoid complex isolatedfrom the seeds of Garcinia kola—in protecting against cuprizone (CPZ)-induced demyelination inboth the prefrontal cortex and the hippocampus of Wistar rats.Methodology: Thirty rats were treated to receive 0.5 mL phosphate-buffered saline (groupA, control), 0.5 mL corn oil (group B), 0.2% CPZ (group C), for 6 weeks, 0.2% CPZ for 3 weeks andthen 200 mg/kg of Kv for 3 weeks (group D), or 200 mg/kg of Kv for 3 weeks followed by 0.2%CPZ for 3 weeks (group E). Rats were assessed for exploratory functions and anxiety-like behaviourbefore being euthanised and perfused transcardially with 4% paraformaldehyde. Prefrontal andhippocampal thin sections were stained in hematoxylin and eosin and cresyl fast violet stains.Results: CPZ-induced demyelination resulted in behavioural impairment as seen byreduced exploratory activities, rearing behaviour, stretch attend posture, center square entry,and anxiogenic characteristics. Degenerative changes including pyknosis, karyorrhexis, neuronalhypertrophy, and reduced Nissl integrity were also seen. Animals treated with Kv showedsignificant improvement in behavioural outcomes and a comparatively normal cytoarchitecturalprofile.Conclusion: Kv provides protective roles against CPZ-induced neurotoxicity throughprevention of ribosomal protein degradation.