Abstract Background This study evaluates the impact of different initial ventilation strategies on in-hospital mortality among sepsis patients. Methods We included hospitalized sepsis patients who underwent mechanical ventilation from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and categorized them into groups based on their initial ventilation strategy: non-invasive ventilation (NIV) and invasive mechanical ventilation (IMV). The main endpoint analyzed was in-hospital mortality. A propensity score matching model was employed to address confounding factors, and Cox survival analysis was performed in the matched cohort. Subgroup analyses were conducted to evaluate population heterogeneity. Results Among 19,796 patients who received mechanical ventilation, 10,073 (50.8%) initially received NIV. The analysis included 2935 matched pairs. Patients initially receiving NIV exhibited a higher survival rate (P = 0.009) and a 24% lower risk of in-hospital mortality compared to those initially receiving IMV (P