Objective <p>This study examined whether the addition of meal replacement (MR)-assisted intermittent fasting increases the effectiveness of a lifestyle intervention.</p> Methods <p>In a nonrandomized intervention study, overweight and obese participants aged 18 to 60 years were recruited for weight management with MRs or lifestyle intervention alone (LIA) for 8 weeks. The outcomes were the percent change in body weight from baseline to weeks 4 and 8 and the associated changes in body composition (using a bioimpedance analyzer). Generalized estimating equation (GEE) models were used to compare outcomes between groups.</p> Results <p>A total of 126 participants were recruited, and 74 participants in the MR group and 46 participants in the LIA group finished the intervention protocol. The mean age was 35.4 ± 9.7 years, and 75.4% were female. The baseline BMI was 26.6 ± 3.7&#xa0;kg/m². At 4 weeks, the percent weight loss in the MR group was 6.3%, whereas it was 4.0% in the LIA group (<i>P</i> &lt; 0.001). At 8 weeks, the percent weight loss in the MR group was 8.2%, whereas it was 5.8% in the LIA group (<i>P</i> = 0.004). The GEE models revealed no further differences in weight loss or related measurements between the groups, whereas the time effect was significant.</p> Conclusions <p>Our study demonstrated that lifestyle interventions can result in weight loss regardless of the use of MR-assisted intermittent fasting. This finding suggests that nutritional support needs to be provided during short-term weight loss interventions.</p> Trial registration <p>Chinese Clinical Trial Registry number: ChiCTR2500099520, Retrospectively registered 25 March 2025.</p>