Background: Post-amputation pain is experienced by 50–80% of patients as residual or phantom limb pain. The transection of nerves during amputation invariably results in the formation of an end neuroma, which has been demonstrated to contribute to the development of post-amputation pain. As a consequence of the pain, there is a reduction in quality of life for patients with impacts upon rehabilitation, prosthetic use, analgesia requirements and mental health. Currently, there are no interventions which have been shown to result in consistent reduction of pain. The advent of regenerative peripheral nerve interface for the neuromodulation of prosthetic devices was coincidentally found to reduce the formation of end neuromas. Methods: We performed a systematic review of the available literature to determine the effectiveness of regenerative peripheral nerve interface in preventing and treating post-amputation residual and phantom limb pain, as well as any effects on analgesia and prosthetic use. Results: Seven papers were included after an initial 2935 papers were identified. All papers demonstrated an improvement in residual and phantom limb pain in their respective prophylactic and treatment groups. One paper demonstrated an improvement in prosthetic adherence, with a further study showing a reduction or no increased requirement of analgesia for all treated patients. Studies demonstrate the effectiveness of RPNI in prophylactic prevention or treatment of post-amputation pain by reduction of neuroma formation. Conclusions: Results of this systematic review suggest that regenerative peripheral nerve interface should be implemented as a minimum gold standard at the time of amputation and as a treatment for intractable post-amputation pain. Level of evidence: Not ratable [ABSTRACT FROM AUTHOR]