Mitochondrial activity is essential for brain function, as ATP produced by mitochondria is crucial for neuronal activity, growth, and regeneration. Bioenergetic failure is a hallmark in neurodegenerative and acquired brain diseases and converts the mitochondria into a molecular target to prevent neuronal death. Mitochondrial regulation can play a crucial role in energetic balance, calcium homeostasis, and neuronal signaling. Different molecules have been implicated in the regulation of this organelle, and recently, the endocannabinoid system (ECS) became a relevant mitochondrial regulator through the mitochondrial CB1 receptor (mtCB1R). The recent discovery of this receptor and its participation in mitochondrial homeostasis opens new insights about its role in neuronal plasticity and neurodegeneration. This review briefly describes the endocannabinoid system, with a major focus on mtCB1R and its role in mitochondrial homeostasis, learning, memory, and neuronal death. Relevant aspects of the role of mtCB1R in the brain in health and diseases remain unclear; however, exploring this topic holds promising implications in the comprehension of mitochondrial degeneration and future therapeutic advantages.