Chronic inflammation is a significant contributor to hypertensive heart failure. Carnosol (Car), primarily derived from the sage plant (Salvia carnosa), exhibits anti-inflammatory properties in a range of systems. Nevertheless, the influence of angiotensin II (Ang II) on cardiac remodeling remains uncharted. Car was shown to protect mice's hearts against Ang II-induced heart damage at dosages of 20 and 40 mg/kg/d. This protection was evident in a concentration-related decrease in the remodeling of the heart and dysfunction. Examination of the transcriptome revealed that the pivotal roles in mediating the protective effects of Car involved inhibiting Ang II-induced inflammation and the activation of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, Car was found to inhibit p38 phosphorylation, therefore reducing the level of inflammation in cultured cardiomyocytes and mouse hearts. This effect was attributed to the direct binding to p38 and inhibition of p38 protein phosphorylation by Car both in vitro and in vivo. In addition, the effects of Car on inflammation were neutralized when p38 was blocked in cardiomyocytes.