Abstract Background The aim of this meta-analysis was to compare the long-term efficacy of diet plus exercise (D + E) vs. diet (D), D + E vs. exercise (E) and D vs. E on anthropometric outcomes and cardiovascular risk factors in overweight and obese participants. Methods Electronic searches were performed in MEDLINE and the Cochrane Central Register of controlled trials. Inclusion criteria were as follows: body mass index ≥25 kg/m 2 and a minimum intervention period including follow-up of ≥12 months. Outcomes of interest were as follows: anthropometric parameters, blood lipids, blood pressure and cardiorespiratory fitness. Pooled effects were calculated using pairwise random effects and Bayesian random effects network meta-analysis. Results of the corresponding fixed effects models were compared in sensitivity analyses. Results Overall, 22 trials (24 reports) met the inclusion criteria and 21 (including 3,521 participants) of them were included in the quantitative analysis. As compared with D, D + E resulted in a significantly more pronounced reduction in body weight [mean differences (MD): -1.38 kg, 95% confidence interval (CI) -1.98 to -0.79], and fat mass (MD: -1.65 kg, 95% CI -2.81 to -0.49], respectively. When comparing D + E with E, MD in change of body weight (-4.13 kg, 95% CI -5.62 to -2.64), waist circumference (-3.00 cm, 95% CI -5.81 to -0.20), and fat mass (-3.60 kg, 95% CI -6.15 to -1.05) was in favour of combined diet and exercise, respectively. Comparing E vs. D, diet resulted in a significantly more pronounced decrease in body weight (MD: -2.93 kg, 95% CI -4.18 to -1.68), and fat mass (MD: -2.20 kg, 95% CI -3.75 to -0.66). D + E yielded also the greatest reductions with respect to blood lipids and blood pressure when compared to single applications of D and E, respectively. Results from the network meta-analyses confirmed these findings. Conclusions Moderate-quality evidence from the present network meta-analysis suggests that D + E can be highly recommended for long-term obesity management. Furthermore, the evidence suggests a moderate superiority of D over E with respect to anthropometric outcomes. Systematic review registration PROSPERO CRD42013003906