Objective To investigate the effect of nicotinamide mononucleotide (NMN) in treatment of cardiac fibrosis in mice and the underlying mechanism. Methods A total of 40 male C57/BL6J mice (8 weeks old) were randomly divided into cardiac fibrosis model group (model group), normal control+normal saline group (control group), model+NMN group and normal control+NMN group, with 10 mice in each group. Mouse model of cardiac fibrosis was established by peritoneal injection of 1.6mg/(kg·d) angiotension Ⅱ (Ang Ⅱ) through subcutaneously implanted Alzet 1004 micropump, and the mice of the control group was pumped with the same amount of normal saline. The changes of echocardiography, blood pressure, cardiac HE staining and Masson staining were observed, and the expression of cardiac fibrosis related genes and proteins in mice were detected by real-time quantitative PCR and Western blot analysis. Results Compared with the control group, the mice in the model group had declined cardiac function and severer cardiac fibrosis, while NMN treatment improved the ejection fraction and attenuated myocardial fibrosis. The expression of SIRT6 was significantly decreased in the model group, and NMN administration up-regulated the expression of the molecule. Conclusion NMN can inhibit the cardiac fibrosis induced by Ang Ⅱ in mice, which may be associated with its up-regulation of SIRT6 expression.