Acute pancreatitis (AP), which causes severe morbidity and mortality, is a heavy burden for people clinically and financially. This study was designed to explore the mechanism of AP and try to find effective therapies against AP. The expression of FXYD5 was interfered by performing transfection. RT-qPCR and Western blot were utilized to measure FXYD5 expression. In addition, the viability, apoptosis and inflammatory response were evaluated using CCK-8, TUNEL and ELISA, respectively. Moreover, Western blot was employed to measure the expressions of apoptosis-, inflammation- and signaling pathway-related proteins. FXYD5 was found to be overexpressed in AP patients and AP cell model. The results showed that in cerulein-induced AR42J cells, cell viability was remarkably increased, and apoptosis was inhibited compared to the normal FXYD5-expressing group because FXYD5 was downregulated. Similarly, in such cells, interference with FXYD5 significantly suppressed the inflammatory response. In addition, Western blot analysis revealed that JAK2/STAT3 signaling was also strongly inhibited by FXYD5 interference. However, the effect of FXYD5 downregulation was reversed upon simultaneous activation of JAK2/STAT3 signaling. In conclusion, downregulation of FXYD5 could promote cell viability and alleviate inflammatory response in cerulein-induced AP via blocking JAK2/STAT3 signaling pathway.