Local pancreatic necrosis and systemic inflammatory response caused by acute pancreatitis (AP) are closely related to the disease prognosis and severity. This study aimed to explore whether pentraxin 3 (PTX3) regulates AP pancreatic necrosis and reveals the underlying mechanism. By using AP time gradient transcriptomics, proteomics and liquid phase chip analysis, we found a close association between PTX3 and AP. Subsequently, caerulein (CAE) induced in vivo AP model and CCK induced in vitro acinar cell damage model were constructed to determine the expression of PTX3 and its regulation of AP. The results showed that PTX3 was highly expressed in the CAE-induced AP model. And more severe pancreatic tissue damage and increased serum amylase were observed after the intervention of recombinant protein PTX3, which was strongly linked to the decreasing in mitochondrial membrane potential, increasing in reactive oxygen species, and regulation by oxidative phosphorylation pathway. PTX3 could exacerbate acinar cell damage in AP by mediating the process of oxidative phosphorylation.