The amplitude of the H‐reflex during the development and progression of fatigue reflects a complex interplay between central and peripheral factors. The purpose of this study is to characterize H‐reflex homosynaptic post‐activation depression (PAD) in an online fashion during a sustained submaximal fatigue task. The task required a high motor output in order to increase the likelihood of creating partial muscle ischemia with accumulation of fatigue metabolites, an important potential inhibitory influence upon the H‐reflex during the progression of fatigue. Eleven subjects without neurologic impairment maintained volitional, isometric plantar flexion at 60% of maximal voluntary contraction until exhaustion. A paired‐pulse stimulus (2 Hz) was delivered to the tibial nerve to elicit paired H‐reflexes before, during, and after the fatigue protocol. The normalized amplitude of the second H‐reflex (depression ratio) served as an estimate of PAD. Depression ratio increased during the first half of the fatigue protocol (P < 0.001), indicating a diminution of PAD, and then returned as exhaustion approached. The biphasic behavior of homosynaptic H‐reflex depression during fatigue to exhaustion suggests a role for metabolic mediators of post‐activation depression during fatigue.