A systematic overview of 14 systematic reviews (SRs) evaluated interventions addressing polypharmacy, including 179 unique studies. The reviews focused on four categories: medication-related process outcomes, clinical and functional outcomes, healthcare use and economic outcomes, and intervention acceptability. Nine SRs found significant reductions in potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs), with improvements in medication appropriateness. Twelve SRs examined clinical and functional outcomes, with mixed results, including no significant effect on mortality, falls, or quality of life. Ten SRs found no significant effect on hospitalizations and readmissions, while two found reductions in emergency department visits. Two SRs found wide variation in the adoption of polypharmacy-related interventions. The study concluded that there is little evidence of an association between polypharmacy-related interventions and reduced important clinical and healthcare use outcomes. More research is needed to determine which interventions are most effective and which populations would benefit most. The findings suggest that while some interventions may reduce PIMs and PPOs, there is limited evidence for their impact on mortality, hospitalizations, or falls. The quality of evidence was generally low, with many studies showing mixed or null effects. The study highlights the need for further research to better understand the effectiveness of polypharmacy interventions.A systematic overview of 14 systematic reviews (SRs) evaluated interventions addressing polypharmacy, including 179 unique studies. The reviews focused on four categories: medication-related process outcomes, clinical and functional outcomes, healthcare use and economic outcomes, and intervention acceptability. Nine SRs found significant reductions in potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs), with improvements in medication appropriateness. Twelve SRs examined clinical and functional outcomes, with mixed results, including no significant effect on mortality, falls, or quality of life. Ten SRs found no significant effect on hospitalizations and readmissions, while two found reductions in emergency department visits. Two SRs found wide variation in the adoption of polypharmacy-related interventions. The study concluded that there is little evidence of an association between polypharmacy-related interventions and reduced important clinical and healthcare use outcomes. More research is needed to determine which interventions are most effective and which populations would benefit most. The findings suggest that while some interventions may reduce PIMs and PPOs, there is limited evidence for their impact on mortality, hospitalizations, or falls. The quality of evidence was generally low, with many studies showing mixed or null effects. The study highlights the need for further research to better understand the effectiveness of polypharmacy interventions.