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Objectives Central nervous system complications of acute pancreatitis (AP) can result in cerebral edema (CE). We assessed the risk of serious outcomes and health care features associated with CE in patients hospitalized with AP. Methods We conducted a retrospective cohort study using the National Inpatient Sample database. Patients were divided into the AP-CE group that developed CE and the AP-only group that did not. Outcome data were analyzed using Stata software. Results Among 543,464 patients hospitalized with AP, 220 (0.04%) developed CE. In multivariate analysis, primary outcomes included increased length of hospital stay (adjusted odds ratio [aOR] 10.1; 95% confidence interval [CI] 0.50–19.70), hospital charges (aOR USD 208,713; 95% CI 27,095–390,330), and risk of death (aOR 17.17; 95% CI 5.88–50.07) in the AP-CE group. Secondary outcomes showed patients with AP-CE had a significantly increased risk of serious complications, particularly cardiac arrest (aOR 64.24; 95% CI 24.27–170.02), and higher hospital resource utilization. Conclusion Patients with AP who develop CE face worse outcomes, including increased mortality risk, prolonged hospital stay, and greater resource utilization. Timely identification and effective management of CE in AP may reduce mortality and ease the health care burden associated with this neurological complication.