Objective To verify whether sodium-glucose cotransporter 2 inhibitor (SGLT2i) can regulate the activation of cardiac fibroblasts (CFs) by changing macrophage paracrine under hypoxic/reoxygenation (H/R) condition, and thus attenuate myocardial fibrosis. Methods A total of 27 C57BL/6 male mice were randomly divided into sham group, ischemia-reperfusion injury (IRI) group and IRI+SGLT2i group, with 9 animals in each groups. In 28 d later, echocardiography and immunofluorescence assay were used to detect myocardial fibrosis and adverse remodeling. RAW264.7 cells were assigned into negative control (NC) group, H/R group and H/R+SGLT2i group. M2 polarization were observed with immunofluorescence assay and Western blotting. Secretion of transforming growth factor beta (TGF-β), interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-ɑ), interleukin 6(IL-6), and platelet-derived growth factor-a (PDGF-a) were measured with enzyme linked immunosorbent assay (ELISA). Primarily cultured mouse CFs were divided into NC group, H/R group and H/R+SGLT2i group. Then macrophage supernatant was added into the culture medium of the CFs to observe the cell activation. GraphPad Prism 8 statistics was used for statistical analysis. Multiple group comparisons were conducted using one-way analysis of variance, while data comparison between two groups was conducted using Tukey′ post hoc test. Results In vivo, echocardiographic findings at 28 d postoperatively showed that the IRI+SGLT2i group exhibited higher left ventricular ejection fraction and left ventricular shortening fraction, whereas lower left ventricular end-systolic volume, left ventricular end-diastolic volume, left ventricular internal systolic diameters, and left ventricular internal diastolic diameters when compared with the IRI group (all P<0.05). Immunofluorescence assay indicated that the IRI+SGLT2i group had reduced contents of type I and type Ⅲ collagen, and Sirius red staining showed a decreased ratio of type I to type Ⅲ collagen compared with the IRI group (P<0.05). In vitro, Western blotting showed that the H/R+SGLT2i group had increased ratio of M2 marker, Arg1, and less ratio of M1 marker, iNOS, compared to the H/R group (P<0.05). ELISA indicated less abundant TGF-β, IL-1β, TNF-ɑ , IL-6 and PDGF-a, were observed in the H/R+SGLT2i group than the H/R group (P<0.05). Western blotting results confirmed that the expression of α-SMA and collagen in the CFs in the H/R+SGLT2i group was lower than that in the H/R group (P<0.05). Conclusion SGLT2i ameliorates IRI-induced myocardial fibrosis. It can inhibit M1 polarization, promote M2 polarization, and suppress the secretion of inflammatory and fibrosis-related cytokines. Its treatment for RAW264.7 cell supernatant can inhibit the activation of CFs. Our findings confirm that SGLT2i suppresses the activation of CFs and improves poor ventricular remodeling by regulating the paracrine secretion of macrophages.