This research was designed to assess the inhibitory action of aliskiren, L-carnitine, and their combined treatment on JAK2/STAT3/SOCS3 signaling pathway in cardiac hypertrophy induced by isoproterenol injection in rats. Wistar rats were injected with isoproterenol (5 mg/kg/day) for 15 days for induction of cardiac hypertrophy. Hypertrophied animals were concurrently treated daily with aliskiren (50 mg/kg) and/or L-carnitine (200 mg/kg). Either L-carnitine or aliskiren treatment significantly reduced the elevated relative heart weight with a concomitant reduction in brain natriuretic peptide, creatine kinase-MB, and troponin T in isoproterenol treated animals. Additionally, L-carnitine and/or aliskiren treatment significantly reduced myocardial interleukin-6, lipid peroxidation, and markedly increased glutathione content. Aliskiren and/or L-carnitine treatment also attenuated myocardial fibrosis as evidenced by the significant decrease in myocardial collagen I and transforming growth factor-β1. The biochemical results were further confirmed by the improvement in myocardial histopathological architecture. Interestingly, aliskiren and L-carnitine treatment down-regulated the expression of JAK2, STAT3, and SOCS3 in hypertrophied animals. Conclusively, aliskiren/L-carnitine regimen may ameliorate cardiac hypertrophy induced by isoproterenol through mitigating oxidative stress, inflammation, and IL-6/JAK2/STAT3/SOCS3 pathway.