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This study compared the acute hypoalgesic and neurophysiological responses to low‐load resistance exercise with and without blood flow restriction (BFR), and free‐flow, high‐load exercise. Participants performed four experimental conditions where they completed baseline measures of pain pressure threshold (PPT), maximum voluntary force (MVF) with peripheral nerve stimulation to determine central and peripheral fatigue. Corticospinal excitability (CSE), corticospinal inhibition and short interval intracortical inhibition (SICI) were estimated with transcranial magnetic stimulation. Participants then performed low‐load leg press exercise at 30% of one‐repetition maximum (LL); low‐load leg press with BFR at 40% (BFR40) or 80% (BFR80) of limb occlusion pressure; or high‐load leg press of four sets of 10 repetitions at 70% one‐repetition maximum (HL). Measurements were repeated at 5, 45 min and 24 h post‐exercise. There were no differences in CSE or SICI between conditions (all P > 0.05); however, corticospinal inhibition was reduced to a greater extent (11%–14%) in all low‐load conditions compared to HL (P < 0.005). PPTs were 12%–16% greater at 5 min post‐exercise in BFR40, BFR80 and HL compared to LL (P ≤ 0.016). Neuromuscular fatigue displayed no clear difference in the magnitude or time course between conditions (all P > 0.05). In summary, low‐load BFR resistance exercise does not induce different acute neurophysiological responses to low‐load, free‐flow exercise but it does promote a greater degree of hypoalgesia and reduces corticospinal inhibition more than high‐load exercise, making it a useful rehabilitation tool. The changes in neurophysiology following exercise were not related to changes in PPT. What is the central question of this study?Does low‐load, blood flow restricted, resistance exercise promote greater hypoalgesic and neurophysiological changes in the 24 h period post‐exercise, in comparison to high‐load resistance exercise?What is the main finding and its importance?Blood flow restriction exercise augments hypoalgesia compared to free‐flow, low‐load exercise and induces similar hypoalgesia to high‐load exercise, but does not result in any different alterations to corticospinal excitability or inhibition. However, corticospinal inhibition was reduced to a greater extent with low‐load exercise, compared to high‐load exercise. Therefore, low‐load BFR resistance exercise is a suitable method for exercise rehabilitation. [ABSTRACT FROM AUTHOR]