This systematic overview evaluates the evidence for interventions addressing polypharmacy, a condition characterized by the regular use of five or more medications. The study aims to update and summarize evidence from multiple systematic reviews (SRs) published between January 2017 and October 2022, as well as those identified in a previous overview (January 2004-February 2017). The evidence is categorized into four outcomes: medication-related process outcomes, clinical and functional outcomes, health care use and economic outcomes, and acceptability of the intervention. **Key Findings:** - **Medication-Related Process Outcomes:** Nine SRs examined these outcomes, finding significant reductions in potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs), as well as improvements in medication appropriateness. - **Clinical and Functional Outcomes:** Twelve SRs assessed these outcomes, with mixed results. Five SRs found no significant effects on mortality, five on falls incidence, and most on quality of life. - **Health Care Use and Economic Outcomes:** Ten SRs reported on hospitalizations and readmissions, with one SR finding significant reductions in hospitalizations and readmissions among higher-intensity medication reviews with face-to-face patient components. Four SRs examined emergency department visits, with two finding reductions. - **Acceptability:** Two SRs assessed the acceptability of the interventions, finding wide variation in adoption rates. **Conclusions:** The updated systematic overview suggests that while polypharmacy interventions show some promise in reducing PIMs and PPOs and improving medication appropriateness, there is limited evidence of their effectiveness in reducing mortality, hospitalizations, readmissions, or falls. More high-quality evidence is needed to identify the most effective interventions and target specific high-risk populations.This systematic overview evaluates the evidence for interventions addressing polypharmacy, a condition characterized by the regular use of five or more medications. The study aims to update and summarize evidence from multiple systematic reviews (SRs) published between January 2017 and October 2022, as well as those identified in a previous overview (January 2004-February 2017). The evidence is categorized into four outcomes: medication-related process outcomes, clinical and functional outcomes, health care use and economic outcomes, and acceptability of the intervention. **Key Findings:** - **Medication-Related Process Outcomes:** Nine SRs examined these outcomes, finding significant reductions in potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs), as well as improvements in medication appropriateness. - **Clinical and Functional Outcomes:** Twelve SRs assessed these outcomes, with mixed results. Five SRs found no significant effects on mortality, five on falls incidence, and most on quality of life. - **Health Care Use and Economic Outcomes:** Ten SRs reported on hospitalizations and readmissions, with one SR finding significant reductions in hospitalizations and readmissions among higher-intensity medication reviews with face-to-face patient components. Four SRs examined emergency department visits, with two finding reductions. - **Acceptability:** Two SRs assessed the acceptability of the interventions, finding wide variation in adoption rates. **Conclusions:** The updated systematic overview suggests that while polypharmacy interventions show some promise in reducing PIMs and PPOs and improving medication appropriateness, there is limited evidence of their effectiveness in reducing mortality, hospitalizations, readmissions, or falls. More high-quality evidence is needed to identify the most effective interventions and target specific high-risk populations.