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Background : Targeted muscle reinnervation (TMR) has been shown to reduce phantom limb pain (PLP) and residual limb pain (RLP) in amputee patients, improving the quality of life. This systematic review aimed to evaluate the quality of data and determine the efficacy of TMR on pain reduction and functional outcomes in amputees. Methods: The protocol was registered and published a priori on PROSPERO (CRD42021285083). Medline, Embase, CENTRAL, Science Citation Index, and PsycINFO databases were searched until June 2022, retrieving 10 studies (n = 943). Selected outcomes were pain scores, improvement in limb function, complication rates, pain medication, and resubmission rates. Results: Ten studies (1 RCT and 9 observational studies) were included (n = 1099 limbs). The mean follow-up was 17.9 months (range 9.6–24.0). For NRS, the pooled mean difference was − 2.68 (95% CI: − 3.21, − 2.14; p < 0.0001) for RLP and − 2.17 (95% CI: − 2.70, − 1.63; p < 0.0001) for PLP, in favor of the TMR group, respectively. Pooled mean differences were significantly lower for all domains (all p < 0.0001) of the PROMIS score, in favor of the TMR group. Complication rates ranged from 0 to 16%. All studies showed a reduction in PLP and RLP following TMR. Three studies, assessing functional outcomes, showed an increase following TMR. The RCT was graded high quality and observational studies were moderate to very low quality. Conclusions: Despite varying study quality, pooled analysis shows a significant reduction in RLP and PLP across all PROMIS domains and significant reduction in NRS scores in the TMR group. Additionally, TMR demonstrated improved functional outcomes for amputees. Systematic review registration. PROSPERO CRD42021285083. Level of evidence: Not gradable [ABSTRACT FROM AUTHOR]