This study investigated skeletal muscle tissue oxygenation (StO2) desaturation in males and females across the adult lifespan. One-hundred-two individuals (51 females) of 41 young, 34 midlife, and 27 older adults completed a vascular occlusion test with near-infrared spectroscopy (NIRS+VOT). This included five minutes of arterial occlusion, inducing transient ischemia in the forearm flexor muscle group while recording StO2. The magnitude of desaturation (StO2mag) was quantified as the difference between baseline StO2 and the minimum StO2 value observed during ischemia. The rate of desaturation was also examined. Forearm adipose tissue thickness (ATT), forearm lean mass, and handgrip muscular strength were measured. A p ≤ 0.05 was considered significant. Two-way between factor ANOVAs indicated that males exhibited significantly (ptextless0.001) less ATT than females (collapsed across age) and that forearm lean mass (ptextless0.001) and muscular strength (ptextless0.001) decreased across the lifespan independent of sex. Bivariate analyses revealed significant (ptextless0.05) associations for sex, age, ATT, forearm lean mass, and muscular strength with the desaturation metrics. The ATT values demonstrated the strongest relations with StO2mag and desaturation rate (r = -0.620 and 0.618). Using a model comparison approach, ATT plus age offered the best predictive power for StO2mag and desaturation rate (R2 = 0.456 and 0.438) such that the inclusion of sex did not improve the models. These findings suggested differences in desaturation were primarily explained by variations in ATT and, to a lesser extent, age, but biological sex had no meaningful effect. Future studies must determine what other factors influence desaturation during ischemia.