Chronic pain is quite prevalent and causes significant disabilities and socioeconomic burdens. Spinal manipulative therapy and other manipulative therapies are used to manage chronic pain. There is a critical knowledge gap about mechanisms and sites of action in spinal manipulative therapy pain relief, especially the short-term analgesia that occurs following a treatment. Endocannabinoids are an activity-dependent neurotransmitter system that acts as a short-term synaptic circuit breaker. This review describes both clinical research and basic research evidence suggesting that endocannabinoids contribute to short-term manipulative therapy analgesia. Determining endocannabinoids involvement in spinal manipulative therapy will improve its clinical efficacy when results from basic science and clinical research are translated.