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Cardiac function and compliance impairments are the features of cardiac fibrosis. Matrine shows therapeutic effects on cardiovascular diseases and organ fibrosis. In this study, we examined the therapeutic effects and mechanisms of matrine on cardiac fibrosis of DbCM. Matrine was administrated orally to rats with DbCM. Cardiac functions and compliance were evaluated. The collagen deposition was visualized by sirius red staining. Real-time PCR was used to determine the expression level of miRNA. Western blotting was performed to assess the protein expression. NFAT nuclear translocation was evaluated by fluorescent immunochemistry staining and Western blotting. Intracellular calcium level was assessed by fura-2/AM staining. A colorimetric method was used to determine calcineurin enzymatic activity. Impaired cardiac function and compliance were observed in rats with DbCM. Increased collagen deposition in cardiac tissue was found. Furthermore, ATF6 signaling was activated, leading to intracellular calcium accumulation and NFAT activation which further initiated ECM gene expressions. Matrine administration recovered cardiac function and improved compliance by exerting inhibitory effects against ATF6 signaling- induced fibrosis. The high- glucose incubation induced ATF6 signaling activation in cultured CFs to increase the synthesis of ECM. Matrine blocked the ATF6 signaling in CFs to inhibit ECM synthesis within non- cytotoxic concentrations. ATF6 signaling induced cardiac fibrosis was one of the mechanisms involved in DbCM, which was characterized by loss of cardiac compliance and functions. Matrine attenuated cardiac compliance and improved left ventricular functions by exerting therapeutic effects against cardiac fibrosis via affecting ATF6 signaling pathway.