Near-infrared diffuse correlation spectroscopy (NIR-DCS) is an optical technique for estimating relative changes in skeletal muscle perfusion during exercise, but may be affected by changes in cutaneous blood flow, as photons emitted by the laser must first pass through the skin. Accordingly, the purpose of this investigation was to examine how increased cutaneous blood flow affects NIR-DCS blood flow index (BFI) at rest and during exercise using a passive whole-body heating protocol that increases cutaneous, but not skeletal muscle, perfusion in the uncovered limb. BFI and cutaneous perfusion (laser Doppler flowmetry) were assessed in 15 healthy young subjects before (e.g., rest) and during 5-minutes of moderate-intensity hand-grip exercise in normothermic conditions and after cutaneous blood flow was elevated via whole-body heating. Hyperthermia significantly increased both cutaneous perfusion (~7.3-fold; p≤0.001) and NIR-DCS BFI (~4.5-fold; p≤0.001). Although relative BFI (i.e., fold-change above baseline) exhibited a typical exponential increase in muscle perfusion during normothermic exercise (2.81±0.95), there was almost no change in BFI during hyperthermic exercise (1.43±0.44). A subset of 8 subjects were subsequently treated with intradermal injection of botulinum toxin-A (Botox) to block heating-induced elevations in cutaneous blood flow, which 1) nearly abolished the hyperthermia-induced increase in BFI, and 2) restored BFI kinetics during hyperthermic exercise to values that were not different from normothermic exercise (p=0.091). Collectively, our results demonstrate that cutaneous blood flow can have a substantial, detrimental impact on NIR-DCS estimates of skeletal muscle perfusion and highlight the need for technical and/or pharmacological advancements to overcome this issue moving forward.