This study examined the effect of aerobic exercise with and without blood flow restriction (BFR) on exercise-induced hypoalgesia and endogenous opioid and endocannabinoid systems. In a randomized crossover design, pain-free individuals performed 20 min of cycling in four experimental trials: 1) low-intensity aerobic exercise (LI-AE) at 40% V O2max; 2) LI-AE with low-pressure BFR (BFR40); 3) LI-AE with high-pressure BFR (BFR80); and 4) high-intensity aerobic exercise (HI-AE) at 70% V O2max. Pressure pain thresholds (PPTs) were assessed before and 5 min postexercise. Circulating concentrations of beta-endorphin and 2-arachidonoylglycerol were assessed before and 10 min postexercise. In the exercising legs, postexercise PPTs were increased following BFR40 and BFR80 compared with LI-AE (23-32% vs. 1-2% increase, respectively). The increase in PPTs was comparable to HIAE (17-20% increase) with BFR40 and greater with BFR80 (30-32% increase). Both BFR80 and HI-AE increased PPTs in remote areas of the body (increase of 26-28% vs. 19-21%, respectively). Postexercise circulating beta-endorphin concentration was increased following BFR40 (11%) and HI-AE (14%), with the greatest change observed following BFR80 (29%). Postexercise circulating 2-arachidonoylglycerol concentration was increased following BFR40 (22%) and BFR80 (20%), with the greatest change observed following HI-AE (57%). Addition of BFR to LI-AE can trigger both local and systemic hypoalgesia that is not observed follow LI-AE alone and activate endogenous opioid and endocannabinoid systems of pain inhibition. Compared with HI-AE, local and systemic hypoalgesia following LI-AE with high-pressure BFR is greater and comparable, respectively. LI-AE with BFR may help pain management in load-compromised individuals.