Herein, 11 general types of natural cannabinoids from Cannabis sativa as well as 50 (-)-CBD analogues with therapeutic potential were described. The underlying molecular mechanisms of CBD as a therapeutic candidate for epilepsy and neurodegenerative diseases were comprehensively clarified. CBD indirectly acts as an endogenous cannabinoid receptor agonist to exert its neuroprotective effects. CBD also promotes neuroprotection through different signal transduction pathways mediated indirectly by cannabinoid receptors. Furthermore, CBD prevents the glycogen synthase kinase 3β (GSK-3β) hyperphosphorylation caused by Aβ and may be developed as a new therapeutic candidate for Alzheimer’s disease. Display omitted •The present review lists 11 general types of natural cannabinoids from Cannabis sativa as well as 50 (-)-CBD analogues.•CBD activate endocannabinoids participated retrograde signals, inhibits the release of Glu to generate a protective response.•For AD treatment, CBD can rescue the production of neurofibrillary tangles and inhibit neuronal apoptosis.