Acute pain elicits a well-known inhibitory effect on upper limb corticomotor excitability, whereas the temporal effects of lower-limb experimental pain and pain in a remote limb are less clear. The aim of this study was to compare the temporal corticomotor excitability changes in the upper and lower limbs in response to acute upper and lower limb pain. In a cross-over design, 13 participants (age 29 ± 9 years; 12 male) attended 2 sessions where experimental pain was induced by injecting hypertonic saline into either the first dorsal interosseous (FDI) muscle or infrapatellar fat pad at the knee, inducing a short-lasting pain experience scored on a numerical rating scale (NRS). Motor evoked potentials (MEPs) in response to transcranial magnetic stimulation were recorded in the FDI and vastus lateralis (VL) muscles before, during, and following pain. Hand and knee pain NRS scores were not significantly different. Hand pain elicited a short duration inhibition of the FDI MEPs (P < .0001) together with a facilitation of VL MEPs (P = .001) that outlasted the duration of pain. Knee pain elicited a short-duration facilitation of VL MEPs (P = .003) with no significant effect in the FDI MEPs (P = .46). The findings indicate a limb-specific corticomotor response to experimental pain that may be related to limb function. PERSPECTIVE: These data demonstrate the impact of acute, experimental pain on corticomotor excitability in the upper and lower limbs. This facilitates our understanding of the effect of pain on motor control of both local and distant muscles.