Lifting-induced fatigue may influence neuromuscular control of spinal stability. Stability is primarily controlled by muscle recruitment, active muscle stiffness, and reflex response. Fatigue has been observed to affect each of these neuromuscular parameters and may therefore affect spinal stability. A biomechanical model of spinal stability was implemented to evaluate the effects of fatigue on spinal stability. The model included a 6-degree-of-freedom representation of the spine controlled by 12 deformable muscles from which muscle recruitment was determined to simultaneously achieve equilibrium and stability. Fatigue-induced reduction in active muscle stiffness necessitated increased antagonistic cocontraction to maintain stability resulting in increased spinal compression with fatigue. Fatigue-induced reduction in force-generating capacity limited the feasible set of muscle recruitment patterns, thereby restricting the estimated stability of the spine. Electromyographic and trunk kinematics from 21 healthy participants were recorded during sudden-load trials in fatigued and unfatigued states. Empirical data supported the model predictions, demonstrating increased antagonistic cocontraction during fatigued exertions. Results suggest that biomechanical factors including spinal load and stability should be considered when performing ergonomic assessments of fatiguing lifting tasks. Potential applications of this research include a biomechanical tool for the design of administrative ergonomic controls in manual materials handling industries.