Background and Aim: The present study was undertaken to investigate the potential of ethyl acetate fraction obtained from the fruits of Xylocarpus moluccensis alcoholic extract (CDR-267-F018) against cardiac hypertrophy in rats. Experimental Procedure: Cardiac hypertrophy was achieved in Wistar rats through isoproterenol and treated either with propranolol or CDR-267-F018 for 14 days. Results and Conclusion: CDR-267-F018 treatment reduced isoproterenol induced cardiac hypertrophy as assessed by 2D-echocardiography and supported by reduction in ANP, BNP, β-MHC, NPP-A and increased expression of vascular endothelial growth factor receptor 1. CDR-267-F018 treatment tightly regulated inflammation by controlling the plasma proinflammatory cytokines tumor necrosis factor-α and IFN-γ, plasma EMP level and NF-κB, Akt and ERK. Further, CDR-267-F018 treatment reduced fibrosis by regulating Col18a1, FGF-21 and MMP2. In total, CDR-267-F018 protected rat heart against isoproterenol induced cardiac hypertrophy by acting on inflammation, fibrosis and by improving angiogenesis.