Background: Serious mental illness (SMI) reduces life expectancy, primarily due to somatic comorbidity linked to obesity. Meta-analyses have found beneficial effects of lifestyle interventions in people with SMI and recommended their implementation to manage obesity. Objective: The objective of this systematic review was to assess the benefits and harms of individualized lifestyle interventions for weight in people diagnosed with SMI and to explore potential mediators and moderators of the effect. Methods: The protocol was registered at PROSPERO (CRD42016049093). Randomized clinical trials (RCTs) assessing the effect of individualized lifestyle interventions on weight management in people with SMI were included. Primary outcomes were differences in endpoint body mass index (BMI) and the proportion achieving clinically relevant weight loss (≥5%). Secondary outcomes included quality of life, cardiometabolic risk factors, and adverse effects. Results: We included 41 RCTs (n = 4,267). All trials were at high risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. The experimental interventions reduced the mean difference in BMI by -0.63 kg/m (95% confidence interval [CI] = -1.02 to -0.23; p = 0.002; I = 70.7%) compared to the control groups. At postintervention follow-up (17 RCTs), the effect size remained similar but was no longer significant (BMI = -0.63 kg/m 95% CI = -1.30 to 0.04; p = 0.07; I = 48.8%). The risk ratio for losing ≥5% of baseline weight was 1.51 (95% CI = 1.07-2.13; p = 0.02) compared to the control groups. GRADE showed very low or low quality of evidence. Conclusion: There is a statistically significant, but clinically insignificant, mean effect of individualized lifestyle interventions for weight reduction in people with SMI.