Aims <p>To conduct a systematic review and meta-analysis comparing tirzepatide <i>versus</i> placebo for weight management, with analyses stratified by diabetes status to precisely assess its efficacy and safety in individuals with and without diabetes.</p> Methods <p>We systematically searched MEDLINE, Embase, and Cochrane Library for randomized controlled trials comparing once-weekly tirzepatide (5–15 mg) <i>versus</i> placebo in adults with or without diabetes for at least 26 weeks. For each subpopulation analysis, the random-effects model was used to calculate pooled risk ratios (RRs) and mean differences (MDs), with their 95% confidence intervals, for dichotomous and continuous endpoints, respectively. Statistical significance was considered at p &lt; 0.05.</p> Results <p>We included five trials (n = 2,174) in patients with diabetes (BMI ≥ 23 kg/m²) and five (n = 4,467) in patients without diabetes (BMI ≥ 27 [≥24 in Asia] kg/m²). Compared with placebo, tirzepatide led to significantly greater relative and absolute weight reductions in patients with (RR −9.54%, p &lt; 0.01; MD −9.06 kg, p &lt; 0.01) and without diabetes (RR −17.15%, p &lt; 0.01; MD −18.11 kg, p &lt; 0.01). In both subpopulations, tirzepatide also significantly increased the probability of achieving weight reductions of ≥5%, ≥10%, and ≥15%, as well as improved BMI, waist circumference, blood pressure, hemoglobin A1c, and lipid levels. Notably, weight-related benefits with tirzepatide were significantly greater in patients without diabetes, whereas its safety was similar across subpopulations and predominantly consisted of mild to moderate, well-tolerated adverse events.</p> Conclusions <p>Compared with placebo, tirzepatide resulted in statistically significant and clinically meaningful weight reduction, especially in patients without diabetes (with overweight/obesity), with an acceptable safety profile.</p>