Importance: Poor outcomes after upper extremity peripheral nerve injury (PNI) may arise, in part, from the challenges and complexities of cortical plasticity. Occupational therapy practitioners need to understand how the brain changes after peripheral injury and how principles of cortical plasticity can be applied to improve rehabilitation for clients with PNI. Objective: To identify the mechanisms of cortical plasticity after PNI and describe how cortical plasticity can contribute to rehabilitation. Data Sources: PubMed and Embase (1900-2017) were searched for articles that addressed either (1) the relationship between PNI and cortical plasticity or (2) rehabilitative interventions based on cortical plastic changes after PNI. Study Selection and Data Collection: PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Articles were selected if they addressed all of the following concepts: human PNI, cortical plasticity, and rehabilitation. Phantom limb pain and sensation were excluded. Findings: Sixty-three articles met the study criteria. The most common evidence level was Level V (46%). We identified four commonly studied mechanisms of cortical plasticity after PNI and the functional implications for each. We found seven rehabilitative interventions based on cortical plasticity: traditional sensory reeducation, activity-based sensory reeducation, selective deafferentation, cross-modal sensory substitution, mirror therapy, mental motor imagery, and action observation with simultaneous peripheral nerve stimulation. Conclusion and Relevance: The seven interventions ranged from theoretically well justified (traditional and activity-based sensory reeducation) to unjustified (selective deafferentation). Overall, articles were heterogeneous and of low quality, and future research should prioritize randomized controlled trials for specific neuropathies, interventions, or cortical plasticity mechanisms.