Occupational nerve injuries span a broad array of pathologies and contribute toward functional limitation, disability, and economic impact. Early and accurate recognition, treatment, and management of workplace factors rely on a thorough understanding of the anatomic and biomechanical factors that drive nerve injury. This review explores the interplay between anatomy, biomechanics, and nerve pathology common to occupational nerve injury and provides the treating physician with a rational, evidence-based approach to diagnosis and to occupational aspects of management. Assessment of potential occupational nerve injury begins with a detailed understanding of the employee's work duties through a biomechanical lens. One must consider likelihood of occupational causation while accounting for predisposing conditions or preexisting symptoms. Beyond overt crush injury or laceration, potential mechanisms of nerve injury, with effects compounded over time, include compression, stretch, vibration, and repetitive or high-force movements of regional muscles and joints. Injury often occurs at nerve locations that experience higher pressures, changes in pressure over time, or abrupt changes in trajectory, often near a tethered point. This understanding, coupled with condition-specific knowledge presented in this review, equips managing physicians to diagnose occupational nerve injury and enhance treatment recommendations with rational activity modifications or equipment that can protect the nerve or decrease likelihood of continued injury. Long-term management often involves follow-up to assess effectiveness of interventions in the setting of the work environment, with gradual progression of the worker toward return to unrestricted duty or to a point of maximal medical improvement.