: Semaglutide (SEMA) has shown potential benefits in metabolic dysfunction-associated steatotic liver disease (MASLD). This large real-world study aimed to evaluate the effects of SEMA on MASLD patients' clinical outcomes and liver-related complications. : Following propensity score matching based on 34 variables (demographics, comorbidities, laboratory tests, and medication history), SEMA-treated ( = 19,112) patients were compared with non-SEMA ( = 19,112) cases. Both cohorts were well-balanced, except for higher BMI in the SEMA group (36.60 ± 6.25 vs. 34.89 ± 6.84 kg/m). After one year, the SEMA group demonstrated ~one BMI point reduction but maintained significantly higher BMI (35.51 ± 6.34 vs. 34.11 ± 6.64, < 0.001). LDL, triglycerides, and HbA1c levels significantly improved with SEMA, as evidenced by decreased rates of poor metabolic markers (31.13% vs. 34.32%, < 0.001). The SEMA-treated patients demonstrated significantly higher survival, lower cardiovascular risk, and reduced progression to advanced liver disease compared to controls. : In this large real-world cohort, SEMA use in MASLD patients was associated with significantly improved 1-year survival, cardiovascular, and liver-related outcomes. These benefits appear to result primarily from metabolic improvements and anti-inflammatory effects. : Data were sourced from TriNetX, a global health research platform with de-identified electronic medical records spanning 135 million patients across 112 healthcare organizations worldwide. We included MASLD adults diagnosed according to ICD9 criteria. Assessed outcomes included survival, biochemical, hematologic, AFP, metabolic and cardiovascular parameters, advanced liver disease (ALD), synthetic function, and metabolic markers. : Semaglutide may serve as an effective therapeutic strategy to improve outcomes in MASLD.