This study aimed to investigate and compare the magnitude of exercise-induced hypoalgesia (EIH) with low-intensity blood flow restriction (BFR) resistance exercise (RE) at varying pressures to other intensities of resistance exercise and examine endogenous mechanisms of pain reduction. Twelve individuals performed four experimental trials involving unilateral leg press exercise in a randomized crossover design: low-load RE at 30% of one repetition maximum (1RM), high-load RE (70% 1RM), and BFR-RE (30% 1RM) at a low and high pressure. BFR pressure was prescribed relative to limb occlusion pressure at 40% and 80% for the low- and high-pressure trials. Pressure pain thresholds (PPT) were assessed before and 5 min and 24 h following exercise in exercising and nonexercising muscles. Venous blood samples were collected at the same timepoints to determine plasma concentrations of beta-endorphin and 2-arachidonoylglycerol. High-pressure BFR-RE increased PPTs in the exercising limb to a greater extent than all other trials. Comparable systemic EIH effects were observed with HLRE and both BFR-RE trials. PPTs in the exercising limb remained elevated above baseline at 24 h postexercise following both BFR-RE trials. Postexercise plasma beta-endorphin concentration was elevated during the BFR-RE trials. No changes to 2-arachidonoylglycerol concentration were observed. High pressure BFR-RE causes a greater EIH response in the exercising limb that persists for up to 24 h following exercise. The reduction in pain sensitivity with BFR-RE is partly driven by endogenous opioid production of beta-endorphin. BFR-RE should be investigated as a possible pain-modulation tool in individuals with acute and chronic pain. NEW & NOTEWORTHY High-pressure blood flow restriction (BFR) causes a greater hypoalgesia response in the exercising limb (48%) compared with light and heavy load resistance exercise (10-34%). Performing light load resistance exercise with BFR causes systemic hypoalgesia comparable with heavy load resistance exercise (10-18%). BFR resistance exercise prolonged the exercise-induced hypoalgesia response for 24 h in the exercising limb (15% and 24%, respectively). Activation of endogenous opioid production and a conditioned pain modulation effect partly mediate the relationship between exercise and hypoalgesia.