Objectives: Decreased mechanical loading after orthopaedic surgery predisposes patients to develop muscle atrophy. The purpose of the study was to assess whether oral protein supplementation can help decrease postoperative muscle atrophy and/or improve patient outcomes following orthopaedic surgery. Methods: A systematic review of the literature was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The review was registered with the Prospective Register of Systematic Reviews (PROSPERO). A search of the PROSPERO registration did not identify similar prior systematic reviews or meta-analyses. Databases were searched during April 2021 and included: MEDLINE (Pubmed), Embase, Scopus, and Web of Science. Each search contained a combination of the following terms: “orthopaedic procedures” AND “protein” OR “amino acid” AND “dietary supplements” OR “supplementation” OR “supplement.” Orthopaedic procedures were listed individually using the PubMed index of orthopaedic procedures, as well as using the mesh function to extract articles with orthopaedic procedures listed as keywords. Eligibility Criteria The principal inclusion criteria consisted of randomized controlled trials evaluating protein or amino acid regimens as a measure to counteract muscle atrophy following orthopaedic surgery. Articles that evaluated other forms of dietary supplementation or non-orthopaedic procedures were excluded. Control groups included either placebo or a natural history control (i.e. routine post-operative protocol). The scope of surgery was intentionally left broad, to allow for a comparison of protein supplementation effectiveness across different surgical interventions. Each study’s reference list was manually reviewed for additional articles to prevent unintentional exclusion of studies. Two reviewers independently assessed all articles identified by the search strategy and applied the eligibility criteria. Data Extraction The content extracted from each article included: (1) demographic data, (2) protein supplement regimen used, (3) outcomes, (4) complications, and (5) length of follow up. Primary outcomes included functional or physiologic measures of muscle atrophy or strength. Secondary outcomes included patient satisfaction and time to return to sport or work. Data Analysis Quality assessment of studies was performed using Modified Coleman Methodology Scoring (MCMS). Heterogeneity of study design was noted including differences in protocols, measurement techniques, and outcomes measured, which prevented an adequate statistical comparison for meta-analysis. Results: Fourteen studies including 611 patients (224 male, 387 female) were analyzed (Figure 1). Four surgical cohorts were identified: Anterior cruciate ligament reconstruction (ACLR), total hip arthroplasty (THA), hip fractures (THA, revision THA, hip resurfacing), and total knee arthroplasty (TKA). The ACLR, THA, and hip fracture cohorts were each composed of 3 studies, while there were 5 studies in the TKA cohort. Average length of follow-up was 9 weeks for ACLR, 7 weeks for THA, 10 weeks for hip fracture, and 7 weeks for TKA. Protein supplementation included various combinations of essential amino acids in tablet form or whey protein powder. Placebo supplements were most commonly an isocaloric carbohydrate tablet or powder. Protein supplementation was reported to have beneficial effects across all types of identified surgeries. The primary benefit was decreased muscle atrophy measured by muscle cross sectional area. The most significant difference in muscle atrophy was observed in the final week of follow-up for the majority of studies (average follow up was 8 weeks). Multiple studies also demonstrated improved functional measures, including increased muscle function measured by isokinetic muscle strength. Of note, most participants were involved in some form of formal physical therapy for varying durations after surgery, but this was not standardized across all studies. There were no significant increases in side effects reported comparing protein supplementation cohorts to controls. Of the included investigations, only 2 studies (both for hip fracture) had participants follow a standardized diet. Average MCMS scores for each surgical cohort were as follows: ACLR 55 (fair), TKA 55 (fair), THA 46 (poor), hip fracture 44 (poor). Conclusions: In conclusion, protein supplementation appears to have beneficial effects on mitigating muscle atrophy in the postoperative period following ACLR, THA, TKA, and surgical treatment of hip fracture. This response often correlates with improved functional measures and quicker achievement of rehabilitation benchmarks. Further research is needed to establish standardized supplementation regimens and guidelines for improving clinical outcomes in the postoperative period.