Context The obesity epidemic is a main driver of the chronic disease epidemic; however, present treatment approaches have suboptimal efficacy. Objectives To assess the efficacy of plant-predominant (vegan, vegetarian, plant-based whole foods [PBWFs]) diets in treating obesity and its main cardiometabolic sequelae: hyperlipidemia (HLD); indices of insulin resistance, glycemic control, and diabetes mellitus type 2 (DM2); and cardiovascular disease (CVD), including hypertension (HTN). Data Sources A systematic search of multiple databases was conducted for articles published between November 2019 and February 2020; databases searched included: PubMed, Medline (Ovid), Cochrane, CENTRAL, and CINAHL. Data Extraction and Analysis All interventional trials (randomized controlled trials [RCTs] and trials of non-randomized experimental design) that met the inclusion criteria (English language, duration of at least 4 weeks, primary end point congruent with above objectives, no major flaws in research design that would prevent interpretation) were included in the review. A total of 3135 articles were scanned and 84 were selected. The articles were collated and summarized in 2 evidence tables. Risk of bias for RCTs was assessed using the Cochrane Risk-of-Bias tool 2 as a guide. For non-randomized trials, higher risk of bias was assumed, and the JBI Critical Appraisal tool was used as a guide to determine inclusion. Results Plant-based diets, in general, demonstrated improved weight control and cardiometabolic outcomes related to lipids, cardiovascular end points, blood pressure, insulin sensitivity, A1C, and fasting glucose, and a lower risk of diabetes compared with usual diets and in some cases standard health-oriented diets such as the American Heart Association (AHA), American Diabetic Association (ADA), and Mediterranean diets. Preliminary studies suggest plant-predominant diets practiced as part of healthy lifestyle interventions may stabilize or even reverse DM 2 and CVD. The acceptability and sustainability of plant-predominant diets where measured were generally similar to other health-oriented diets. Conclusion Plant-predominant diets can play a major role in reversing the obesity and chronic disease epidemics. In the setting of sustained lifestyle intervention programs, they may arrest or even reverse DM2 and CVD. Further higher-level RCTs are needed to confirm and expand on these findings.