The tumor suppressor p53 is inactivated in over half of all cancers via genetic mutation or MDM2-mediated degradation. However, these events rarely occur in some cancers such as neuroblastoma, suggesting there may be other ways tumors suppress p53 function. We identify KDM5A, a H3K4me3/me2 histone demethylase, as a novel regulator of p53 signaling through translational regulation of p53 expression via modulation of eukaryotic translation initiation. The expression of KDM5A tends to be higher in p53 wild-type tumors. Importantly, loss of KDM5A significantly reduces p53+/+, but not p53-/- or mutant p53, tumor growth. Thus, our findings reveal a novel regulatory mechanism of p53 function and suggest KDM5A as a new target for the treatment of tumors expressing wild-type p53.