Muscle pain is an important determinant of exercise tolerance, but its relationship with neurophysiological responses during a submaximal exercise trial is unclear. The purpose of this study was to determine the effect of persistent contralateral pain on neurophysiological function and perceptual responses during, ipsilateral isometric knee extensions to task failure. Ten participants performed a single-leg repeated submaximal isometric knee extensions with (PAIN) or without (CTRL) constant pain induced by intermittent blood flow occlusion combined with evoked muscle contraction applied to the contralateral, resting leg. Transcranial magnetic stimulation (TMS) applied over the motor cortex was used to assess corticospinal excitability (quantified as motor evoked potentials), corticospinal inhibition (quantified as silent period duration), and short interval intracortical inhibition. Maximal voluntary contractions (MVCs), coupled with femoral nerve stimulation to the exercising leg, were performed every 12 submaximal contractions to assess neuromuscular function. Perceived leg pain and effort were also assessed throughout the exercise. The experimental pain shortened the time to task failure compared to CTRL (P=0.019). Although time effects were present, no differences appeared between conditions for MVC force, voluntary activation, or potentiated twitch force across both tasks (all P>0.05). Additionally, no differences between CTRL and PAIN were demonstrated for any TMS-derived measures assessing corticospinal responses. Exercising leg pain was higher in CTRL (P=0.018), as was perceived exertion (P=0.030). Overall, when using a persistent, submaximal experimental pain intervention, it appears that although muscle pain compromises exercise tolerance, this phenomenon occurs independently of potential alterations and corticomotor mechanisms.