Objective To detect the serum levels of ghrelin, amylase (AMS), and high-sensitivity C-reactive protein (hs-CRP) in patients with severe acute pancreatitis (SAP) complicated by intra-abdominal infection and to analyze their prognostic values.Methods A total of 58 patients with SAP and intra-abdominal infection treated in our hospital from May 2016 to May 2019 were selected as the observation group, while 116 SAP patients without intra-abdominal infection were included as the control group. The serum levels of ghrelin, AMS and hs-CRP were compared between the two groups. According to the outcome 28 days after admission, the patients in the observation group were further divided into survival group (40 cases) and death group (18 cases), and the serum levels of ghrelin, AMS, and hs-CRP, Ranson score, and Multiple Organ Dysfunction (MOD) score were compared between the two subgroups. Pearson correlation method was used to analyze the relationship between each serum indicator and Ranson and MOD scores. Logistic regression analysis was used to determine the factors affecting the prognosis of SAP combined with intra-abdominal infection. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of serum Ghrelin, AMS, and hs-CRP for the prognosis of patients with SAP combined with intra-abdominal infection, and Kaplan-Meier curve was used for survival analysis.Results The serum levels of ghrelin, AMS and hs-CRP in the observation group were higher than those in the control group (P < 0.05). There was no difference in the cause of the disease, the pathogens, or the combination of underlying disease between the survival group and the death group (P > 0.05). However, the age, the incidence of multiple organ dysfunction, and the incidence of hypoxemia were different between the survival group and death group (P < 0.05), and the differences of serum levels of ghrelin, AMS and hs-CRP, Ranson score, and MOD score before and after the treatment were greater in the survival group relative to the death group (P < 0.05). After 5 days from the confirmed diagnosis of infection, the serum levels of ghrelin, AMS, and hs-CRP were all positively correlated with the Ranson score (r =0.570, 0.515, and 0.650, all P <0.05) and MOD score (r = 0.657, 0.745, 0.527; all P < 0.05). Logistic regression analysis showed that age > 50 years [O^R = 1.937 (95% CI: 1.215, 3.087)], multiple organ dysfunction [O^R = 3.384 (95% CI: 2.332, 4.911)], hypoxemia [O^R = 2.021 (95% CI: 1.308, 3.124)], ghrelin [O^R = 2.994 (95% CI: 1.706, 5.253)], AMS [O^R = 3.109 (95% CI: 2.041, 4.736)], hs-CRP [O^R = 3.863 (95% CI: 2.455, 6.079)], Ranson score [O^R = 3.544 (95% CI: 2.118, 5.931)], and MOD score [O^R = 4.297 (95% CI: 2.704, 6.829)] were factors affecting the combination with intra-abdominal infection in SAP (P < 0.05). The area under the ROC curve (AUC) of hs-CRP for predicting the prognosis was 0.819 (95% CI: 0.535, 0.789) at 5 days after the diagnosis of infection, with a sensitivity of 61.11% (95% CI: 36.14%, 81.74%) and a specificity of 70.00% (95% CI: 53.29%, 82.91%) when the cut-off value was 334.71 ng/L. The AUC of AMS for predicting the prognosis was 0.775 (95% CI: 0.646, 0.874), with a sensitivity of 88.89% (95% CI: 63.93%, 98.05%) and a specificity of 62.50% (95% CI: 45.81%, 76.83%) when the cut-off value was 330.56 U/L. In addition, the AUC of ghrelin for predicting the prognosis was 0.671 (95% CI: 0.646, 0.874), with a sensitivity of 72.22% (95% CI: 46.41%, 89.29%) and a specificity of 87.50% (95% CI: 72.40%, 95.31%) when the cut-off value was 32.22 mg/L. Kaplan-Meier curve exhibited that the survival was different among patients with high or low levels of ghrelin, AMS, and hs-CRP (P < 0.05).Conclusions Serum ghrelin, AMS and hs-CRP are greatly elevated in SAP patients with intra-abdominal infection, and are closely related to the severity of the disease. Thus, they can be established as essential predictors for the prognosis of SAP complicated by intra-abdominal infection.