Objective Cardiac hypertrophy is an adaptive reaction of the heart against cardiac overloading, but continuous cardiac hypertrophy can lead to cardiac remodeling and heart failure. Cardiac hypertrophy is mostly considered reversible, and recent studies have indicated that decorin not only prevents cardiac fibrosis associated with hypertension, but also achieves therapeutic effects by blocking fibrosis-related signaling pathways. However, the mechanism of action of decorin remains unknown and unconfirmed. Methods We determined the degree of myocardial hypertrophy by measuring the ratios of the heart weight/body weight and left ventricular weight/body weight, histological analysis and immunohistochemistry. Western blotting was performed to detect the expression levels of CaMKII, p-CaMKII and MEF-2 in the heart. Results Our results confirmed that decorin can regulate the CaMKII/MEF-2 signaling pathway, with inhibition thereof being similar to that of decorin in reducing cardiac hypertrophy. Conclusion Taken together, the results of the present study showed that decorin induced cardiac hypertrophy by regulating the CaMKII/MEF-2 signaling pathway in vivo, revealing a new therapeutic approach for the prevention of cardiac hypertrophy.