Objective To explore the clinical value of serum homocysteine (Hcy) combined with C-reactive protein (CRP) and fibrinogen (FIB) in assessing disease severity and prognosis of patients with acute pancreatitis (AP). Methods A retrospective analysis was performed on the clinical data of 217 patients with AP admitted from February 2019 to May 2021. According to disease severity, they were divided into mild AP group (MAP, n=149) and non-mild AP group (NMAP, n=68). According to prognosis, they were divided into good prognosis group and poor prognosis group. The baseline data, levels of Hcy, CRP and FIB in different groups were compared. The prognostic value of Hcy, CRP and FIB was analyzed by receiver operating characteristic (ROC) curves. The risk factors of poor prognosis in AP patients were screened out by multivariate Logistic regression analysis. Results There were significant differences between MAP group and NMAP group in admission to ICU, HB, Ca, CREA, BG, LDH, Hcy, CRP and FIB (P<0.05). There were significant differences between good prognosis group and poor prognosis group in admission to ICU, Hcy, CRP and FIB (P<0.05). Spearman correlation analysis showed that level of serum Hcy was positively correlated with CRP and FIB (P<0.05), level of serum CRP was positively correlated with FIB (P<0.05). ROC curves analysis showed that AUC of Hcy combined with CRP and FIB for predicting prognosis of AP patients was 0.839, greater than that of Hcy, CRP and FIB alone (0.684, 0.678, 0.669) (P<0.05). The results of multivariate Logistic regression analysis showed that admission to ICU (OR=50.222, P=0.013), Hcy >13.32 μmol/L (OR=3.550, P=0.016), CRP >88.96 mg/L (OR=7.218, P=0.001) and FIB >5.22 g/L (OR=4.812, P=0.005) were independent risk factors of poor prognosis in AP patients (P<0.05).Conclusion Serum Hcy, CRP, and FIB levels in patients with acute pancreatitis are elevated, and these three have higher value in predicting the condition and prognosis of AP patients