The purpose was to test the hypothesis that sex and fatigue effect of the early phase of skeletal muscle tissue oxygenation (StO2, %) desaturation rate as well as that strength matched adults may exhibit similar responses. Twenty-four adults visited the laboratory twice to quantify this early phase of desaturation during vascular occlusion tests (VOT) while in a rested state. The second visit included a sustained handgrip task at 25% of maximal muscular strength until task failure. At failure, a post-task VOT was initiated. Muscle desaturation was defined as StO2 and collected by a near-infrared spectroscopy device. The muscle size and adipose thickness were determined via ultrasonography. Linear regression was used to quantify the rates of desaturation during the VOTs as well as during the fatiguing handgrip. There were sex differences in the rate of desaturation pre- and post-handgrip, such that independent of fatigue, the men (p < 0.001) desaturated more rapidly than the women (pre: b = − 0.208 vs. − 0.123%∙s−1; post: − 0.079 vs. − 0.070%∙s−1). During the fatiguing handgrip, the transformed StO2 values indicated that the males desaturated more rapidly than the females (b = − 0.070 vs. − 0.015). The matched pairs exhibited the same responses as the total sample. Overall, muscle size and strength as well as adipose tissue were likely not the primary cause of the differences in rates of muscle desaturation. We hypothesized that differences in fiber type and mitochondria were the principle mechanisms provoking the differences in muscle oxygenation.