Prior exercise has previously been shown to impair subsequent endurance performance in non-activated muscles. Declines in the neuromuscular function and altered perceptual/affective responses offer possible mechanisms through which endurance performance may be limited in these remote muscle groups. We thus conducted two experiments to better understand these performance-limiting mechanisms. In the first experiment, we examined the effect of prior handgrip exercise on the behavioral, perceptual, and affective responses to a sustained, sub-maximal contraction of the knee extensors. In the second experiment, transcranial magnetic stimulation was used to assess the neuromuscular function of the knee extensors before and after the handgrip exercise. The results of the first experiment demonstrated prior handgrip exercise increased the perceptions of effort and reduced affective valence during the subsequent knee extensor endurance exercise. Both effort and affect were associated with endurance performance. Subjective ratings of fatigue were also increased by the preceding handgrip exercise but were not directly related to knee extensor endurance performance. However, perceptions of fatigue were correlated with heightened effort perception and reduced affect during the knee extensor contraction. In the second experiment, prior handgrip exercise did not significantly alter the neuromuscular function of the knee extensors. The findings of the present study indicate that motor performance in the lower limbs following demanding exercise in the upper body appears to be regulated by complex, cognitive-emotional interactions, which may emerge independent of altered neuromuscular function. Subjective fatigue states are implicated in the control of perceptual and affective processes responsible for the regulation of endurance performance.