We compared the minute-by-minute muscle activity and oxygenation responses to a repetitive arm motioninduced fatiguing task between the sexes in order to address the literature gap on these time-dependent fatigue responses. Twenty-six (13 females) healthy adults performed a repetitive pointing task (RPT) with the arm moving forward/backward at shoulder height until reaching 8/10 (Borg CR10) for neck/shoulder perceived exertion (RPE). Neck/shoulder RPE, oxygenation and electromyography were recorded every minute and compared between first and second half of the task and between the sexes. Greater changes in oxygen supply and activation amplitude occurred during the second half of the task. Despite similar time to fatigue-terminal (p > 0.05), females showed greater anterior deltoid activation amplitude at all time points than males, and only the males showed increases in anterior and posterior deltoid activation amplitudes. In females, middle (q = –0.34, p = 0.04) and posterior (q = –0.44, p = 0.01) deltoid amplitudes were negatively correlated with perceived exertion during the first half of the task. Results suggest that reduced modulation of anterior deltoid activation amplitude in females may reflect a sub-optimal fatigue-mitigation mechanism compared with males and may help explain their greater susceptibility to neck/shoulder musculoskeletal disorders.