Objective To analyze the differential diagnostic value of serum CA19-9, mucin 5AC (MUC5AC), and exocytosis Ephrin type A receptor 2 (Exo-EphA2) for pancreatic adenocarcinoma and mass-type pancreatitis, and the correlation with imaging pathological features. Methods A total of 82 patients with pancreatic cancer who were treated in Zhoukou Central Hospital from January 2022 to June 2023 were selected as the observation group, and 41 patients with mass pancreatitis were selected as the control group during the same period. The diagnostic values of the 2 groups and the different pathological parameters of serum CA19-9, MUC5AC, and Exo-EphA2 were compared to analyze their diagnostic values and to analyze the correlation further. Results Serum CA19-9, MUC5AC, and Exo-EphA2 levels were significantly increased in the study group compared with the control group (P<0.05). Comparison of serum CA19-9, MUC5AC, and Exo-EphA2 levels in patients with pancreatic cancer of different pathological parameters. Low differentiation was higher than middle and high differentiation, stage Ⅰ~Ⅱ was lower than Ⅲ~Ⅳ, and distant metastasis was higher than no distant metastasis (P<0.05). The levels of CA19-9, MUC5AC and Exo-EphA2 were positively correlated with distant metastasis and TNM stage, and negatively correlated with the degree of differentiation (P<0.05). The AUC for the combined diagnosis of pancreatic cancer with serum CA19-9, MUC5AC and Exo-EphA2 levels was 0.802, which was higher than that of each index alone. Conclusion There is a relationship between serum CA19-9, MUC5AC, and Exo-EphA2 levels and pathological parameters of pancreatic cancer, and the combined test can significantly enhance the differential diagnostic value in pancreatic cancer and mass-type pancreatic cancer.