It has been suggested that trimethylamine N-oxide (TMAO) is associated with increased risk of diabetes and cardiovascular disease (CVD) morbidity and mortality. However, it is not known whether increased TMAO concentrations is associated with obesity. In the current study, we summarized the evidence related to the association of circulating TMAO with the risk of obesity measurements, including body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) in a two-class and dose-response meta-analysis of observational studies. A systematic search carried out in PubMed, SCOPUS, Cochrane, and ProQuest through September 30, 2019 resulted in 12 eligible studies which were included in the current meta-synthesis. In these studies, BMI was reported but there were no reports of WC or WHR. Meta-analysis of two-class variables and dose-response meta-analysis of continuous variables were performed. Subgroup analysis and meta-regression were also performed to identify the source of heterogeneity. There was a dose-response association between circulating TMAO concentration and increased BMI in studies involving healthy individuals (P nonlinearity = .007), while no evidence of departure from linearity was observed according to study design or among patients with CVD. Results showed the highest category of TMAO was associated with 0.56 kg/m increase in BMI (weighted mean difference [WMD], 0.563; CI, 0.026-1.100; P = .04). The results of the current meta-analysis revealed a positive association between circulating TMAO and obesity as presented by increased BMI. Moreover, a dose-dependent association between circulating TMAO and obesity was also identified in apparently healthy individuals. This is the first meta-analysis to reveal positive dose-dependent associations between circulating TMAO concentration and obesity.