Previous studies have identified some sex differences in how individual muscles change their activation during repetitive multi-joint arm motion-induced fatigue. However, little is known about how indicators of multi-muscle coordination change with fatigue in males and females. Fifty-six (29 females) asymptomatic young adults performed a repetitive, forward-backward pointing task until scoring 8/10 on a Borg CR10 scale while surface electromyographic activity of upper trapezius, anterior deltoid, biceps brachii, and triceps brachii was recorded. Activation coefficient, synergy structure, and relative weight of each muscle within synergies were calculated using the non-negative matrix factorization method. Two muscle synergies were extracted from the fatiguing task. The synergy structures were mostly preserved after fatigue, while the activation coefficients were altered. A significant Sex × Fatigue interaction effect showed more use of the anterior deltoid in males especially before fatigue in synergy 1 during shoulder stabilization (p = 0.04). As for synergy 2, it was characterized by variations in the relative weight of biceps, which was higher by 16 % in females compared to males (p = 0.04), and increased with fatigue (p = 0.03) during the elbow flexion acceleration phase and the deceleration phase of the backward pointing movement. Findings suggest that both sexes adapted to fatigue similarly, using fixed synergy structures, with alterations in synergy activation patterns and relative weights of individual muscles. Results support previous findings of an important role for the biceps and anterior deltoid in explaining sex differences in patterns of repetitive motion-induced upper limb fatigue.