Neuroblastoma (NB) is a type of tumor usually found in children under 5 years of age, which originates from lesions in the nervous system and has fast growth and early transformation characteristics. Similar to other cancer types, some typical tumor suppressor genes (TSGs), such as P53 and CHD5 are silenced in NB because of high methylation at promoter zones. In the present study, our results showed that genistein, an element found in soy, is an epigenetic modifier able to decrease hypermethylation levels of CHD5, and enhances the expression of CHD5 as well as p53, possibly contributing to inhibition of NB growth in vivo and tumor microvessel formation. Furthermore, genistein acts as a DNA methyltransferase (DNMT) inhibitor to significantly decrease the expression of DNMT3b. Our study indicates that genistein plays an important role in inhibiting NB growth in vivo, probably preventing tumorigenesis risk as a kind of therapeutic agent for NB treatment in the future.