ACE2 can regulate the development of intestinal inflammatory response, while the effect on LPS-induced inflammatory changes in porcine intestinal epithelial cells is still unclear. The present study investigated the role of ACE2 in inflammatory injury and the possible signaling pathways. The current results show that LPS cause inflammatory damage in IPEC-J2 cells and local RAS system was activated, with a significant correlation. ACE2 gene of IPEC-J2 cells are knocked down, and the inflammatory response are aggravated. ACE2 resist LPS-induced inflammation by degrading Ang II to produce Ang (1–7). The anti-inflammatory effect of ACE2 are mainly achieved by regulating the phosphorylation level of p65 in the NF-κB pathway and ERK1/2 in the MAPK pathway, reducing the expression and release of cellular inflammatory factors. These results reveal the biochemical mechanism of ACE2 against cellular inflammatory response and its potential application.