Cardiac fibrosis is one of the leading causes of heart failure and therapeutic options are limited. Among various Indian herbal preparations for treating cardiac ailments, the commonly used one is the bark extract of the Terminalia arjuna (Roxb) tree but the mechanisms of actions are unknown. To evaluate its therapeutic potential against cardiac fibrosis, male Wistar rats were injected with isoproterenol (5 mg/ kg) for 8-12 weeks and the aqueous TA extract was administered orally. Twodimensional M-mode echocardiography showed partial restoration of cardiac function by TA. Isoproterenol increased the transcript level of pro-fibrotic genes like Col1α, Col3α, Tgf-β1, and CTGF and TA extract significantly attenuated it. TA extract also increased the activities of antioxidant enzymes catalase and SOD; the levels of GSH content as well as reduced the levels of lipid peroxidation. Increased DNA binding activities of redox sensitive transcription factors NF-κB, and AP-1 in isoproterenol treated heart was partially reversed by the TA extract. Also, the antioxidant response element binding activity of the transcription factor Nrf2 was enhanced by the TA extract in ISO-induced fibrotic rat heart. This study for the first time demonstrates that in ISO-induced fibrotic heart, TA extract improves cardiac function by regulating various gene regulatory modules.