Neurodegenerative diseases are a complex ensemble of ailments characterized by progressive neuronal deterioration and ultimate loss, resulting in drastic impairments of memory, cognition and other brain functions. These incapacitating conditions are challenging for the public health system worldwide, with unfortunately no real cure and lack of efficient drugs capable of delaying or reversing these diseases. In this context, the endocannabinoid system and exogenous cannabinoids represent an interesting field of research due to numerous studies highlighting the neuroprotective effect of cannabinoids from different sources, i.e., endogenous, phytocannabinoids, and synthetic cannabinoids. This review highlights the multilayered effects of cannabinoids and the endocannabinoid system to block the progression of neurodegeneration and minimize the deleterious effects of insults that affect the brain. We illustrate examples showing that the main effects of cannabinoids modulate different components of the brain response to these insults at the level of three major mechanisms involved in neurodegeneration: neuroinflammation, excitotoxicity, and oxidative stress.