In this systematic review, the authors synthesized evidence on polypharmacy in older adults and subsequent adverse health outcomes, as well as impacts on social outcomes (e.g., loneliness), medication management (e.g., nonadherence) and healthcare utilization. Results from twenty-six reviews encompassing 230 unique studies showed that polypharmacy is associated with increased hospitalizations and inappropriate prescribing. The authors describe conflicting evidence on associating polypharmacy with adverse outcomes, including adverse drug events and disability. Evidence on the adverse social outcomes, as well as harms in adults 85 years and older, was limited.