The aim of this study was to investigate the possible ameliorating effects of agomelatine (AGO) on lipopolysaccharide (LPS)-induced endothelial and cardiac damage. Twenty-four female Wistar Albino rats divided into 3 groups as follows: Control, LPS and LPS + AGO. Total oxidant status (TOS), total antioxidant status (TAS), nuclear factor kappa beta (NF-kβ)/p65, p-NF-kβ, full caspase-8 (Cas-8) and cleaved cas-8 levels were measured in cardiac tissues and creatine kinase MB (CKMB), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) levels in blood biochemically. In addition; cas-8, sirtuin-1 (SIRT-1), interleukin-4 (IL-4), interleukin-10 (IL-10), haptoglobin measured histopathologically in cardiac and aortic tissues. The levels of CKMB, AST, LDH and TOS were increased and TAS were decreased in the LPS group. In Western blot analyses NF-kβ/p65, p-NF-kβ/p65, full and cleaved cas-8 protein levels increased in cardiac tissues of LPS group. In histopathological and immunohistochemical evaluation of the heart sections; hyperemia, micro-hemorrhages and inflammatory cell infiltrations, increase of cas-8, haptoglobin, IL-4 and IL-10 and decrease of SIRT-1 levels were observed in cardiac and endothelial tissues of LPS groups. AGO treatment reversed all these parameters. It was shown that LPS-induced inflammation, oxidative stress and apoptosis via increasing of NF-kβ/p65 signaling, decreasing of SIRT-1 levels and increase of cas-8 levels in heart and endothelial tissues respectively. AGO corrected all these parameters by its antioxidant, antiinflammatory and antiapoptotic activities.