Objective To investigate the correlation between the serum level of fibroblast growth factor-21 (FGF-21) and disease severity in acute pancreatitis patients, and to analyze the predictive value of FGF-21 for the risk of death in critical patients.Methods The 160 cases of acute pancreatitis patients admitted to our hospital from February 2017 to July 2019 were included as the acute pancreatitis group, and were further divided into mild group (n = 64), moderately severe group (n = 61), and severe group (n = 35) according to the severity of their conditions. Another 110 healthy volunteers who underwent the physical examination in our hospital during the same period were selected as the normal control group. The level of serum FGF-21 was compared between the acute pancreatitis group and the normal control group. The levels of amylase, C-reactive protein (CRP), and procalcitonin (PCT), and the score of Acute Physiology and Chronic Health Evaluation (APACHE II) were compared among acute pancreatitis patients with different conditions and patients with different survival outcomes in the severe group. The Pearson correlation method was applied to evaluate the relationship between serum FGF-21 and the condition of acute pancreatitis patients. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of FGF-21 for the death risk of patients in the severe group.Results The serum level of FGF-21 was higher in the acute pancreatitis group than that in the normal control group (P < 0.05). The serum levels of amylase, CRP and PCT, as well as the score of APACHE II increased as the condition of acute pancreatitis aggravated (P < 0.05). The serum FGF-21 level was positively correlated with the serum levels of amylase, CRP, and PCT, and the score of APACHE II in acute pancreatitis patients (r = 0.673, 0.701, 0.599 and 0.637; all P < 0.05). Among the severe group, the serum levels of FGF-21, amylase, CRP and PCT, and the score of APACHE II were even lower in those who survived compared with those who died (P < 0.05). The optimal cut-off point of the level of FGF-21 for predicting the death of severe patients within 90 days was 9.35 pg/ml, with a sensitivity of 83.33% (95% CI: 0.794, 0.897) and a specificity of 56.52% (95% CI: 0.538, 0.614).Conclusions The serum level of FGF-21 is highly elevated in acute pancreatitis patients, and plays roles in assessing the condition of the patients and predicting the risk of death in severe patients.