BACKGROUND: Sepsis-associated encephalopathy (SAE), a severe neurological complication of systemic infection, carries substantial morbidity and mortality risks. This study aims to examine the relationship between early acetaminophen use and survival rates in critically ill SAE patients. METHODS: Using data from the MIMIC-IV database, we conducted a retrospective cohort study on patients with SAE, stratified by acetaminophen exposure within 48 h of ICU admission. Among the 4111 eligible patients (1689 acetaminophen recipients versus 2422 non-recipients), propensity score matching resulted in 3124 matched subjects (1562 per cohort). The primary outcome was 90-day mortality, while secondary outcomes included mortality rates at 30, 60, 180, and 365 days. Survival analyses utilized Cox proportional hazards regression and Kaplan-Meier curves, supplemented by subgroup analyses for 90-day mortality. RESULTS: Acetaminophen exposure was correlated with reduced 30-day mortality rate (HR = 0.78, 95%CI [0.65-0.94], p < 0.05), as well as decreased 60-day (HR = 0.71, 95%CI [0.60-0.83], p < 0.001), 90-day (HR = 0.70, 95%CI [0.60-0.81], p < 0.001), 180-day (HR = 0.70, 95%CI [0.60-0.80], p < 0.001) and 365-day (HR = 0.69, 95%CI [0.61-0.79], p < 0.001) mortality rate after PSM. The Kaplan-Meier analysis demonstrated significantly higher survival rates in the acetaminophen group compared to the non-acetaminophen group, with a persistent trend at 30, 90, 180, and 365 days (log-rank p < 0.05). The protective effect was consistent across subgroups except acetaminophen dosage ≥ 650 mg. CONCLUSION: Early administration of acetaminophen is associated with reduced short- and long-term mortality in SAE patients. These findings support a potential therapeutic role for acetaminophen in SAE and warrant further mechanistic and prospective validation.