Objective To investigate the effects of roflumilast (RM) on cardiac remodeling induced by pressure overload in mice and its mechanism. Methods Aortic constriction (AB) was used to construct a mice model of cardiac remodeling. A total of 40 male C57/B6 mice (8-10 weeks) were randomly divided into sham group, AB group, AB + RM (1mg / kg) group, and AB + RM (3mg/kg) group (n=10each). At d 2 after AB surgery, the mice were given an intragastric administration of RM for 6 weeks. Echocardiography was performed to detect cardiac function in each group, including left ventricular ejection fraction (LVEF), left ventricular short axis fraction shortening (LVFS), left ventricular end systolic diameter (LVESD), and left ventricular end diastolic diameter (LVEDD). HE and Picrosirius Red staining were used to observe cardiac hypertrophy and fibrosis, and qPCR was used to detect the mRNA expression levels of cardiac hypertrophy, fibrosis and inflammation-related genes, including atriopeptin, brain natriuretic peptide, β-MHC, connective tissue growth factor, fibronectin, collagen 1,collagan 3, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Immunohistochemical markers CD45 and CD68 were used to detect leukocyte and macrophage infiltration in cardiac tissue. Western blot was used to detect the protein expression level of phosphorylated p38 (P-p38) and total p38 (T-p38). Results At week 6 after AB surgery, compared with the Sham group, LVEF and LVFS in the AB group were significantly reduced, the LVESD and LVEDD were significantly increased, the cardiac hypertrophy and fibrosis were significantly increased, and CD45 and CD68 in cardiac tissue, the expression levels of IL-6 and TNF-α were significantly increased (P<0.05). Compared with the AB group, the cardiac function of the AB+RM (1mg/kg) group and the AB+RM (3mg/kg) group was significantly improved, cardiac hypertrophy and fibrosis were significantly suppressed, and inflammation was significantly reduced (P<0.05). Western blot results showed that RM (1 and 3mg/kg) could significantly inhibit the p38 of cardiac tissue induced by AB surgery (P<0.05). Conclusion Roflumilast can reduce overload-induced cardiac hypertrophy and fibrosis in mice mainly through regulating the p38 MAPK signaling pathway and inflammatory response.