Obesity is a worldwide problem and is associated with multiple negative health effects. Obesity also has a direct relationship with risk of diabetes. Several pharmacotherapy weight-reducing interventions have been employed to prevent type 2 diabetes (T2D) in overweight or obese adults and older adults. However, data with respect to comparative effectiveness are limited. To address this gap, in this study, evidence on benefits of anti-obesity agents for preventing diabetes will be systematically reviewed using a network meta-analysis. We will perform an online systematic search for randomized controlled trials (RCTs) investigating 5 FDA-approved anti-obesity agents for preventing T2D in obese or overweight adults and older adults through electronic databases of PubMed, Embase, and the Cochrane Library from inception until December 31, 2020. Two independent reviewers will screen titles, abstracts, and full-texts of all potentially eligible trials. Two authors working independently will abstract data on trial-, participant- and intervention-related characteristics. The primary outcome will be incidence of T2D. Secondary outcomes will be achievement of normoglycaemia in patients with prediabetes, percentage of individuals achieving at least 5% or 10% weight loss of their baseline weight. We will conduct pairwise meta-analyses for all outcomes included in this study. To determine comparative efficacy of multiple interventions, network meta-analysis with a frequentist random-effects model will be performed. Moreover, subgroup analyses and sensitivity analyses will be performed to assess the robustness of our findings. To evaluate publication bias, the comparison-adjusted funnel plot will be utilized. Stata version 14.0 and RevMan version 5.3.3 will be used to perform all statistical analyses. This study will evaluate the effectiveness of weight-loss medications on T2D prevention in overweight or obese people. This study will generate meaningful findings for overweight or obese adults and older adults, clinicians, and policy-makers concerning the optimal anti-obesity pharmacotherapy to decrease risk of T2D. INPLASY202110104. Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.