Significance: Cannabinoids and their endogenous counterparts, the so-called endocannabinoids, promote neuroprotection in laboratory animals by engaging CB ₁ cannabinoid receptors, one of the most abundant types of receptors in the brain. However, the assessment of the physiological relevance and therapeutic potential of the CB ₁ receptor in neurological diseases is hampered, at least in part, by the lack of knowledge of the neuron-population specificity of CB ₁ receptor action. This study shows that a unique and well-defined population of CB ₁ receptors, namely that located on glutamatergic terminals, plays a key neuroprotective role in the mouse brain. This finding opens a new conceptual view on how the CB ₁ receptor evokes neuroprotection, and provides preclinical support for improving the development of cannabinoid-based neuroprotective therapies.