Shoulder problems are highly prevalent among manual wheelchair users with spinal cord injury, affecting their functioning and quality of life. This study investigates the impact of fatigue on wheelchair propulsion technique and shoulder loading in manual wheelchair users (MWU) with SCI. Twelve MWU with a paraplegia performed a standardized fatiguing wheelchair propulsion protocol; a biomechanical assessment of treadmill propulsion was obtained before and after the fatiguing protocol. Rate of perceived exertion (RPE), upper extremity kinematics, and wheelchair propulsion kinetics were assessed. Results showed increased RPE post-fatigue, with no significant changes in exerted forces but increased thorax forward lean and range of motion. Musculoskeletal modelling showed elevated glenohumeral joint contact force and muscle forces post-fatigue. These findings suggest a potential link between fatigue, altered propulsion technique, and increased shoulder loading, highlighting the risk of overuse injuries. Moreover, increased thorax motion during propulsion may indicate fatigue onset. Prospective cohort studies are warranted to validate the presented findings and explore the relationship between shoulder loading and injury risk. Understanding these dynamics can inform interventions to mitigate shoulder pain and enhance the well-being of MWU with SCI.