BACKGROUND AND AIM: The impact of fluoxetine on serum lipid remains unclear due to inconsistencies in study findings. Differences in intervention duration, participant characteristics, and dosages may contribute to these variations. This meta-analysis and systematic review assessed fluoxetine's effects on lipid profiles in overweight or obese individuals. METHODS: A literature search was employed in Scopus, PubMed/Medline, Web of Science, and Embase for studies published up to December 2024. The DerSimonian and Laird random-effects model was used to estimate pooled weighted mean differences (WMD) and 95% confidence intervals (CI). RESULTS: Nine studies met the inclusion criteria. Fluoxetine significantly reduced triglycerides (TG) (WMD: -22.04 mg/dL
CI: -42.61 to -1.46
P = 0.036) and increased HDL-C (WMD: 2.25 mg/dL
CI: 0.21 to 4.28
P = 0.030). No significant changes were noted in total cholesterol (TC) (WMD: 4.75 mg/dL
CI: -2.576 to 12.08
P = 0.204) or LDL-C (WMD: -0.35 mg/dL
CI: -11.15 to 10.44
P = 0.949). Greater TG reductions occurred with 60 mg/day fluoxetine (WMD: -43.86 mg/dL), baseline TG levels ≥ 150 mg/dL (WMD: -26.62 mg/dL), and interventions lasting ≤ 12 weeks (WMD: -26.88 mg/dL). CONCLUSION: Fluoxetine significantly lowers TG and raises HDL-C in overweight or obese individuals. The effect on TG is more pronounced at 60 mg/day and in shorter interventions. Further research is needed to evaluate long-term impacts.