Metabolic dysfunction–associated steatotic liver disease (MASLD) is a persistent hepatic condition linked with cardiovascular disorders and metabolic disturbances. Characterized by inflammation, fat accumulation, and fibrosis within the liver, MASLD can develop into liver cancer and cirrhosis. With a global prevalence of 32.4%, the condition parallels rising obesity rates. Orlistat inhibits lipase enzymes and, therefore, reduces dietary fat absorption, which may benefit MASLD patients. The present systematic review and meta-analysis were performed in accordance with PRISMA guidelines. Searches of PubMed, Scopus, Web of Science, and Embase up to January 2025 were performed using specific keywords and MeSH terms. Bias assessment and data extraction were conducted using Joanna Briggs Institute (JBI) tools independently by two researchers. Statistical analyses were performed with Stata version 14, calculating standardized mean differences, 95% confidence intervals (CI), and heterogeneity (by performing Cochran’s Q test and I² index). Moreover, metaregression, subgroup analyses, and sensitivity analyses were conducted. Eleven studies featuring 582 participants were included. Orlistat treatment induced a significant reduction in levels of alanine transaminase (ALT) (SMD = -26.23; 95% CI = -34.70 to -17.76) and aspartate aminotransferase (AST) (SMD = -19.62; 95% CI = -28.33 to -10.92). Furthermore, reductions in HOMA-IR, body mass index,cholesterol, insulin, and waist circumference were observed. The included studies exhibited low to moderate heterogeneity for most outcomes, indicating consistent results across trials. Orlistat significantly improved AST, ALT, and some other metabolic parameters in MASLD patients, suggest-ing its potential as an additional treatment option. However, the outcome must be interpreted cautiously, considering study heterogeneity. Further high-quality, multicenter research is necessary to confirm these results.