Background: Rigorous evidence to guide deprescribing is limited, and priorities to inform deprescribing research and practice remain unclear. The objective of this overview of systematic reviews (i.e. reviews) was to synthesize the available review evidence regarding the effectiveness of interventions to deprescribe medications in older adults. Methods 11 databases were searched from January 2005 to October 2020. We included randomized or non-randomized controlled designs. Two independent reviewers screened and extracted data. We synthesized results in two steps: Step 1 identified results as reported by the original review (including meta-analyses) and Step 2 involved a narrative synthesis of reviews by outcome. Pre-specified subgroups included patient characteristics (e.g., dementia, frailty, advanced age), intervention type and setting. Outcomes included medication-related outcomes (e.g., medication reduction, potentially inappropriate medications) or other outcomes(e.g., mortality, adverse effects, falls, cognition, hospitalizations, quality of life, costs, surrogate biomarkers). Assessment of Multiple Systematic Reviews 2 was used to assess quality of reviews. RESULTS: 2,335 unique citations were retrieved, of which 93 full-text articles were assessed for eligibility. 33 reviews (encompassing 13 meta-analyses) were included. 19 of the 33 reviews had a general deprescribing focus, 13 focused on specific medication classes or therapeutic category and one review included both. Ten of 13 reviews meta-analyzed medication-related outcomes (29 outcomes: 21 favored the intervention, seven reported no difference and one favored the comparison). The narrative synthesis indicated that most interventions resulted in some evidence of medication reduction. Few meta-analyses reported on other outcomes, and our narrative synthesis found primarily mixed effects or no evidence of an effect on these outcomes. Limited information was available for patient characteristic subgroups. All reviews scored low or critically low on quality assessment. CONCLUSIONS: Deprescribing interventions likely resulted in medication reduction. Information about other outcomes was not routinely examined, and where included, studies were likely underpowered. The evidence, though of low quality, suggests deprescribing was not associated with increased adverse events, and had little evidence of effect on mortality, quality of life and health-care use. Future research should focus on designing studies powered to examine harms, patient-centered outcomes and the effects on vulnerable subgroups. Systematic Review Registration PROSPERO CRD42020178860 This study was supported by NIA (1R24AG064025).