Microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme that converts prostaglandin H2 to prostaglandin E2 (PGE2), plays an important role in a variety of inflammatory diseases. We investigated the contribution of mPGES-1 to renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) for 7 days using wild type (WT) and mPGES-1 knockout (KO) mice. UUO induced increased mRNA and protein expression of mPGES-1 and cyclooxygenase-2 in WT mice. UUO was associated with increased renal PGE2 content and upregulated PGE2 receptor (EP) 4 expression in obstructed kidneys of both WT and KO mice; EP4 expression levels were higher in KO mice with UUO than that in WT mice. Protein expression of NLRP3 inflammasomes components ASC and interleukin-1β was significantly increased in obstructed kidneys of KO mice compared with that in WT mice. mRNA expressions of fibronectin, collagen III, and transforming growth factor-β1 (TGF-β1) were significantly higher in obstructed kidneys of KO mice than that in WT mice. In mPGES-1 KO mice, protein expression of fibronectin and collagen III was markedly increased in obstructed kidneys when compared with WT mice, which was associated with increased phosphorylation of protein kinase B (AKT). EP4 agonist CAY10598 attenuated increased expression of collagen I and fibronectin induced by TGF-β1 in inner medullary collecting duct 3 cells. Moreover, CAY10598 prevented the activation of NLRP3 inflammasomes induced by angiotensin II in human proximal tubule cells (HK2). In conclusion, these findings suggested that mPGES-1 exerts a potentially protective effect against renal fibrosis and inflammation induced by UUO in mice.