This systematic review with meta-analyses assessed the effects of total diet replacement (TDR) programs on mental well-being in clinical trial participants with a body mass index greater than or equal to 25 kg/m 2 . TDR programs involve replacing all dietary requirements with nutritionally replete formula foods and are generally administered to induce rapid weight loss. To date, it is largely unclear what effects TDR programs may have on mental well-being, particularly in the long-term. To address this, we screened 25,976 references across six databases and extracted 35 publications. These 35 publications provided sufficient data to evaluate the effects of TDR programs on depression, anxiety, stress, positive affect, negative affect, vitality, role-emotional, social functioning, mental health, mental composite summary score, self-esteem, and general psychological health in 24 meta-analyses.Due to the lack of research comparing TDR programs to comparator groups, 22 of our 24 meta-analyses explored change in these mental well-being sub-domains over time in TDR programs without comparators. Specifically, we assessed the change from pre-diet (before the TDR program) to either post-diet (up to and including two months after the TDR program); and/or follow-up (more than two months after the TDR program). For depression and anxiety, we were also able to assess the change from pre-diet to mid-diet (which fell within two weeks of the diet half-way point). The remaining two meta-analyses assessed the difference in depression scores between a TDR group and a food-based comparator group from pre-diet to post-diet and from pre-diet to follow-up. Across all meta-analyses, our results found no marked adverse effects of TDR programs on any mental well-being sub-domain. In fact, clear improvements were observed for depression, anxiety, stress, vitality, role-emotional, and social functioning at post-diet. Interestingly, the improvements for depression, vitality and role-emotional were maintained at follow-up. All improvements were