OBJECTIVE Obesity and related co-morbidities lead to a decrease in health-related quality of life (HRQOL) and mood. Lifestyle strategies may improve these outcomes. However, the efficacy of exercise in conjunction with a weight-loss diet on HRQOL and mood is unclear. The aim of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to examine whether the addition of exercise to energy-restricted dietary programs improves HRQOL and mood status when compared with energy-restricted diets alone in overweight and obese adults. METHODS Eligible RCTs were identified by searching PubMed/MEDLINE, EMBASE, ISI (Web of sciences), Scopus, and Google Scholar up to April 2021. Summary effects were derived using a random-effects model. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. RESULTS The meta-analysis revealed that an energy-restricted diet plus exercise compared with an energy-restricted diet alone had no significant effects on depression (n = 6, hedges'g = - 0.04, 95% CI: - 0.28,0.20), MOS 36-Item Short-Form Health Survey (SF-36)-physical component summary scores (n = 8, weighted mean difference (WMD) = 1.51, 95% CI: - 0.16, 3.18), SF36-mental component summary scores (n = 7, WMD = 0.64, 95% CI: - 1.00, 2.28), and HRQOL disease-specific questionnaire scores (n = 5, hedges'g = 0.16, 95% CI: - 0.09, 0.40). The GRADE revealed that the quality of evidence was low for disease-specific HRQOL scores, and depression status; and high for physical and mental health assessed by SF-36. CONCLUSIONS In our sample of overweight and obese adults, no beneficial effect of adding exercise to an energy-restricted diet was found in terms of HRQOL and Depression.