Women exhibit an attenuated exercise pressor reflex (EPR) when compared to men. The influence of sex-specific mechanisms related to the EPR and performance fatigability remain to be fully elucidated. The purpose was to determine the impact of oxygenation and metabolic efficiency on sex-specific performance fatigability and increases in mean arterial pressure (MAP) resulting from a fatiguing isometric handgrip (IHG). Twenty-four adults volunteered to perform an IHG at 25% at maximal voluntary isometric contractions (MVICs). Pre- and posttest MVICs were conducted to quantify performance fatigability. MAP was collected at 3 timepoints. A near-infrared spectroscopy device was attached to the forearm to derive the following signals: oxy[haem], deoxy[haem], total[haem], and diff[haem]. These values were normalized and examined across time in 5% segments of time-to-task-failure. Metabolic efficiency was defined as the ratio force:deoxy[haem]. During the IHG, there was a decline in oxy[haem] for the men (b = −0.075), whereas the women demonstrated an increase (b = 0.117). For the men, the diff[haem] tracked the mean oxy[haem] response, but there was no change for the women. The men exhibited greater declines in metabolic efficiency, yet there were no sex differences in PF (46.6 ± 9.7% vs. 45.5 ± 14.2%). For relative MAP, the men (24.5 ± 15.1%) exhibited a greater (p = .03) increase than the women (11.0 ± 17.6%). These results indicated the EPR was more prominent for the men, perhaps due to differences in mechanical stimuli and a lack of ability to maintain metabolic efficiency. However, these physiological differences did not induce a sex difference in performance fatigability.