Cell-free DNA (cfDNA) promoter hypermethylation shows promise as a blood-based biomarker for pancreatic cancer, and similar alterations may occur in acute pancreatitis (AP). This study investigated the cfDNA hypermethylation profile of AP patients over time, compared with healthy controls, and its association with AP severity markers. A prospective longitudinal study including hospitalized AP patients and healthy controls was conducted. Methylation-specific PCR of a 23-gene panel was performed on plasma collected at inclusion (T0), 6 weeks (T6W), 6 months (T6M), and 7–8 years (T8Y). Associations between gene hypermethylation and clinical markers of AP severity—CRP, leukocyte count, creatinine, hospital stay, and complications—were evaluated. AP patients had a significantly higher mean number of hypermethylated genes at T0 (7.4, 95% CI: 6.8–8.0) compared with the controls (3.3, 95% CI: 2.8–3.8; p < 0.01). The mean number decreased over time to 3.2 (95% CI: 2.4–4.1) at T8Y. Total hypermethylation was positively associated with CRP (ρ = 0.39; p = 0.0018), leukocytes (ρ = 0.35; p = 0.0052), and hospital stay (ρ = 0.27; p = 0.0375). AP patients exhibited significantly higher cfDNA hypermethylation at disease onset, which normalized over time. Total hypermethylation showed positive associations with several markers of AP severity.