Background: Older adults with multiple chronic diseases commonly require complex medication regimes. When combined with frailty, cognitive impairment, and changing pharmacological prescriptions, older adults’ polymedication regimes increase the risk of medication-related problems (MRPs) and hospitalization. Effective, well-organized medication management could avoid MRPs and their clinical outcomes. Objective: Identify medication management models and analyze their impact on managing and preventing MRPs for polymedicated, home-dwelling older adults. Methods: We will conduct a systematic review of published articles in relevant professional scientific journals from inception until March 31, 2019, in the following electronic databases,: Embase; Medline OvidSP; PubMed (NOT Medline[sb]); Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO; PsycINFO OvidSP; Cochrane Library, Wiley; and Web of Science. We will also hand search the bibliographies of all the relevant articles found and search for unpublished studies. We will consider publications in English, French, German, Spanish, Italian, and Portuguese. Retrieved articles will be screened for eligibility. Statistical analyses will be conducted following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) statements. Data will be analyzed using SPSS Statistics for Windows, version 25.0 (IBM Corp), and Review Manager, version 5.5 (The Nordic Cochrane Centre, The Cochrane Collaboration). Results: A preliminary search in Embase delivered 3272 references. This preliminary search allows us to complete our research strategy with equation development and to search the other databases. Relevant articles identified will allow for searching the reference lists for unpublished studies. The inclusion and exclusion criteria will be rigorously respected in the study selection. The entire study is expected to be completed by January 2020. Conclusions: This review will provide an exhaustive view of medication management models that could be effective for polymedicated, home-dwelling older adults and will allow us to analyze their impact on managing and preventing MRPs.