Recent studies showed hepatoprotective, neuroprotective, and immunomodulatory properties of polyprenols isolated from the green verdure of Picea abies (L.) Karst. This study aimed to investigate effects of polyprenols on oligodendrogenesis, neurogenesis, and myelin content in the cuprizone demyelination model. Demyelination was induced by 0.5% cuprizone in CD‐1 mice during 10 weeks. Nine cuprizone‐treated animals received daily injections of polyprenols intraperitoneally at a dose of 12‐mg/kg body weight during Weeks 6–10. Nine control animals and other nine cuprizone‐treated received sham oil injections. At Week 10, brain sections were stained for myelin basic protein, neuro‐glial antigen‐2, and doublecortin to evaluate demyelination, oligodendrogenesis, and neurogenesis. Cuprizone administration caused a decrease in myelin basic protein in the corpus callosum, cortex, hippocampus, and the caudate putamen compared with the controls. Oligodendrogenesis was increased, and neurogenesis in the subventricular zone and the dentate gyrus of the hippocampus was decreased in the cuprizone‐treated group compared with the controls. Mice treated with cuprizone and polyprenols did not show significant demyelination and differences in oligodendrogenesis and neurogenesis as compared with the controls. Our results suggest that polyprenols can halt demyelination, restore impaired neurogenesis, and mitigate reactive overproduction of oligodendrocytes caused by cuprizone neurotoxicity.