Interventions to address polypharmacy in community-dwelling older adults often focus on medication-related outcomes. The aim was to explore the impact of multidisciplinary interventions to manage polypharmacy on clinical outcomes for community-dwelling older adults. This systematic review and meta-analysis included randomized controlled trials (RCTs) on interventions by at least a pharmacist and a physician, indexed in MEDLINE, EMBASE or CENTRAL up to January 2023. Evidence certainty was assessed using the GRADE approach. Seventeen RCTs were included. Fifteen were rated as 'high' risk of bias. No relevant benefits were found in functional and cognitive status (primary outcomes), falls, mortality, quality of life, patient satisfaction, hospital admissions, emergency department or primary care visits. Interventions reduced medication costs, improved medication appropriateness (odds ratio [OR] 0.39), reduced number of medications (mean difference [MD] -0.57), resolved medication-related problems (MD -0.45), and improved medication adherence (relative risk [RR] 1.14). There was a low or very low certainty of the evidence for most outcomes. Multidisciplinary interventions to address polypharmacy appear effective in improving multiple dimensions of medication use. However, evidence for corresponding improvements in functional or cognitive status is scarce. New efficient models of multidisciplinary interventions to address polypharmacy impacting clinical outcomes should be explored.