The human neck is a unique mechanical structure, highly flexible but fatigue prone. The rising prevalence of neck pain and chronic injuries has been attributed to increasing exposure to fatigue loading in activities such as prolonged sedentary work and overuse of electronic devices. However, a causal relationship between fatigue and musculoskeletal mechanical changes remains elusive. This work aimed to establish this relationship through a unique experiment design, inspired by a cantilever beam mechanical model of the neck, and an orchestrated deployment of advanced motion-force measurement technologies including dynamic stereo-radiographic imaging. As a group of 24 subjects performed sustained-till-exhaustion neck exertions in varied positions—neutral, extended, and flexed, their cervical spine musculoskeletal responses were measured. Data verified the occurrence of fatigue and revealed fatigue-induced neck deflection which increased cervical lordosis or kyphosis by 4–5° to 11°, depending on the neck position. This finding and its interpretations render a renewed understanding of muscle fatigue from a more unified motor control perspective as well as profound implications on neck pain and injury prevention.