The pathophysiology of acute pancreatitis remains poorly understood, and it is a severe inflammatory pancreatic disease that is becoming more widespread globally. The protein orosomucoid 2 (ORM2) is closely linked with tissue injury and inflammation. The purpose of this study was to investigate ORM2 expression in pancreatic acinar cells and its potential regulatory function in the regulation of inflammation and damage in acute pancreatitis. The model was established by culturing rat pancreatic acinar AR42J cells with 10 nM azuretin. Lentivirus was used to transfect AR42J cells to generate negative control and ORM2 knockdown cell lines. In order to track changes in ORM2 expression, cell proliferation, apoptosis, and the production of inflammatory cytokines in AR42J cells, this study carried out a number of tests. Western blotting showed expression changes in the p38 mitogen-activated protein kinases (MAPK) pathway. The results showed that ORM2 expression is up-regulated in acute pancreatitis in vitro, and knocking down ORM2 reversed the decrease in survival rate, the increase in apoptosis and the elevated inflammatory factor levels in AR42J cells induced by cerulein. Knockdown of ORM2 also inhibited the phosphorylation of p38 and extracellular signal-regulated kinase (ERK). In summary, ORM2 may significantly influence damage and inflammation in the in vitro rat pancreatic acinar cells model of acute pancreatitis by modulating the phosphorylation levels of p38 MAPK signaling.