Patients hospitalized with severe mental illness (SMI) often have an unhealthy lifestyle. Changing their sedentary behavior and deficiency in physical activity is challenging and effective interventions are lacking. We evaluated changes in sedentary behavior, physical activity, metabolic health and psychotic symptoms after 18 months of Multidisciplinary Lifestyle enhancing Treatment for Inpatients with SMI (MULTI) compared to treatment as usual (TAU) and explored mediation by change in total activity. We measured sedentary behavior and physical activity using accelerometry (ActiGraph GT3X+), reflected in total activity counts. Data on metabolic health and psychotic symptoms were retrieved from routine screening data within our cohort of inpatients with SMI. Of 65 patients receiving MULTI versus 43 receiving TAU, data were analyzed using linear and logistic multilevel regression, adjusting for baseline values of outcome and differences between groups. Compared to TAU, in which no improvements were observed, we found significantly (p < 0.05) improved total activity (B = 0.5 standardized total activity counts per hour), moderate-to-vigorous physical activity (B = 1.8%), weight (B = −4.2 kg), abdominal girth (B = −3.5 cm), systolic blood pressure (B = −8.0 mmHg) and HDL cholesterol (B = 0.1 mmol/l). No changes in psychotic symptoms were observed. Changes in total activity did not mediate metabolic improvements, suggesting that multiple components of MULTI contribute to these improvements. In contrast to previously unsuccessful attempts to change lifestyle behavior in inpatients with SMI in the longer term, MULTI showed to be a feasible treatment to sustainably improve PA and metabolic health.