This study quantified sex-specific biomechanical adaptations to fatigue in asymmetric lifting. Twenty-one females and fifteen males performed a prolonged asymmetric lifting protocol while upper body, trunk and pelvis kinematics were collected. Features of movement identified with principal component analysis, and peak joint angular velocities and moments were calculated. Sex-specific kinematic adaptations to fatigue included females adopting a ‘stoop-like’ lifting strategy to a greater extent than males. Additionally, females exhibited higher vertical elbow positions during load rotation, moved their body toward the destination for load deposit, and did not reduce peak right shoulder flexion velocities, in contrast to male participants. Females also had greater low back and shoulder peak normalized joint moments. When fatigued, females adopted an asymmetric lifting strategy that minimized metabolic demand as supported by smaller decreases in maximum voluntary contractions. However, females' fatigue-related adaptations increased biomechanical exposures associated with injury risk.