Objective <p>Polypharmacy and long-term preventive medication use are common in frail older adults with limited life expectancy, despite uncertain benefits and potential risks. This systematic review and meta-analysis synthesized evidence on the effect of deprescribing preventive medications (antihypertensives, statins, anticoagulants, and antidiabetic agents) compared to continuation on clinical, physiological, safety, and patient-centered outcomes among older adults with advanced frailty, dementia, or limited life expectancy.</p> Methods <p>PubMed, Embase, Cochrane Library, Web of Science, CINAHL, and ProQuest Dissertations &amp; Theses Global were searched for eligible randomized controlled trials and observational studies. The primary outcome was all-cause mortality. Secondary outcomes were hospitalization, major adverse cardiovascular events (MACE), changes in blood pressure, risks of fractures and falls, and quality of life. Data were pooled (relative risk [RR] or mean difference or standardized mean difference) using random-effects models (RevMan version 5.4). The evidence certainty was evaluated by the GRADE framework (PROSPERO ID: CRD420251147086).</p> Results <p>From 10,397 records, 15 studies (&gt; 33,000 participants) were included. Overall, deprescribing was not associated with increased risk of all-cause mortality (RR: 1.15, 95% CI: 0.98–1.35, I²: 93%), hospitalization (RR: 0.93, 95% CI: 0.82–1.07, I²: 68%), or MACE (RR: 1.37, 95% CI: 0.70–2.70, I²: 95%) (certainty: very low GRADE). Deprescribing was also not associated with increased risks of fracture, fall, or deterioration of quality of life, but with slightly increased systolic blood pressure (deprescribing antihypertensives).</p> Conclusion <p>Deprescribing preventive medications in frail or palliative older adults was not associated with worse outcomes; however, evidence certainty was very low, and further studies are needed.</p>