This study investigated the effects of fatiguing unilateral exercise on the ipsilateral, exercised, and contralateral, non-exercised limb’s post-exercise performance in males and females. Ten males and ten females performed a fatiguing, unilateral isometric leg extension at 50% maximal voluntary isometric contraction (MVIC) force. Prior to and immediately after the fatiguing tasks, MVICs were performed for the exercised and non-exercised limb, with surface electromyographic (sEMG) and mechanomyography (sMMG) amplitude (AMP) and mean power frequency (MPF) recorded from each limb’s vastus lateralis. There were no fatigue-induced, sex-dependent, differences in time to task failure (p= 0.265) or ipsilateral performance fatigability (p= 0.437). However, there was a limb by time interaction (p< 0.001) which indicated decreases in MVIC force of the ipsilateral, exercised (p< 0.001), but not the contralateral, non-exercised limb (p= 0.962). There were no sex-dependent, fatigue-induced differences in neurophysiological outcomes between the limbs (p> 0.05), but there was a fatigue-induced difference in sEMG MPF (p= 0.005). To summarize, there were no differences in fatigability between males and females. Moreover, there was insufficient evidence to support the presence of a general crossover effect following submaximal unilateral isometric exercise. However, independent of sex, the neurophysiological outcomes suggested that competing inputs from the nervous system may influence the performance of both limbs following unilateral fatigue.