Introduction: Painful neuromas are a common postoperative complication of limb amputation often treated with secondary reinnervation. Surgical reinnervation include Targeted Muscle Reinnervation (TMR) and Regenerative Peripheral Nerve Interface (RPNI), and can be primary and secondary. The aim of this review is to assess the effects of primary TMR/RPNI at the time of limb amputation on the incidence and intensity of post-operative neuroma and pain. Methods: This review was registered a priori on PROSPERO (CRD42021264360). A search of the following databases was performed in June 2021: Medline, EMBASE, and CENTRAL. Unpublished trials were searched using clinicaltrials.gov. All randomized and non-randomized studies assessing amputation with a reinnervation strategy (TMR, RPNI) were included. Outcomes evaluated included the incidences of painful neuroma, phantom limb pain (PLP), residual limb pain (RLP), as well as severity of pain, and Pain intensity, behavior, and interference (PROMIS). Results: Eleven studies were included in this systematic review, and five observational studies for quantitative synthesis. Observational study evidence suggests that TMR/RPNI results in a statistically significant reduction in incidence, pain scores and PROMIS scores of PLP and RLP. Decreased incidence of neuromas favored primary TMR/RPNI, but this did not achieve statistical significance (p = 0.07). Included studies had moderate to critical risk of bias. Conclusion: The observational data suggests that primary TMR/RPNI reduces incidence, pain scores and PROMIS scores of PLP and RLP. Going forward, randomized trials are warranted to evaluate this research question, particularly to improve the certainty of evidence.