Background: Salvianolate is the main water-soluble bioactive compound of Salvia Miltiorrhiza Bunge and is now clinically used in the treatment of cardiovascular diseases in China. However, its applications in the prevention of atrial interstitial fibrosis (AIF) and atrial fibrillation (AF) are not fully revealed. Purposes: To investigate the preventive effect of salvianolate on the pathogenesis of AF in post-myocardial infarction (MI) rats and to elucidate the potential mechanisms. Materials and methods: Rats underwent left anterior descending coronary artery ligation were randomized into four groups and administered intraperitoneally with vehicle (MI group, n=13), or 10, 20 and 40 mg/kg salvianolate (Sal-L, Sal-M and Sal-H group, n=13, 14 and 13 respectively) for totally five weeks. Rats underwent sham operation was used as control group (Sham, n=10). Then, echocardiography and AF inducibility test were detected. Tissues and serum were collected for Sirius red and fast green counter stain or hematoxylin-eosin to assess atrial interstitial fibrosis and hypertrophy, or for western blot and ELISA analysis. Results: Salvianolate injection significantly improved cardiac function, reduced left atrial enlargement and Pwave duration, and decreased not only the vulnerability to AF but also AF duration. Histologic analysis showed that salvianolate mitigated AIF and atrial hypertrophy. Western blot analysis found that salvianolate inhibited the TGF beta 1/Smad2/3 mediated-collagen deposition and inhibited the TXNIP/NLRP3 inflammasome/IL-1 beta and IL-18 signal pathway. ELISA analysis showed that salvianolate significantly reduced the serum concentrations of BNP, IL-6, CRP and TGF beta 1. Conclusions: Salvianolate may constitute a novel upstream therapy for AF by suppressing AIF. The underlying mechanism may be attributable to its inhibitory effects on TGF-beta 1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathway.