CP-31398 activates wild-type p53 by a novel mechanism that does not involve phosphorylation of the amino-terminus of p53 and disassociation of MDM2. To identify more potent CP-31398-like p53 activators, we synthesized 4 acridine derivatives with a similar structure to CP-31398. These four compounds induced strong p53 transcription in cells with wild-type p53. We also found that several randomly chosen acridine derivatives, including 9-aminoacridine, amsacrine, quinacrine and acridine orange, induced p53 transcriptional activity. All these acridine derivatives stabilized p53 protein by blocking its ubiquitination, without phosphorylation of ser15 or ser20 on p53. Furthermore, acridine derivatives induced p53-dependent cell death. Knockout of Bax, a p53 target and a key cell death inducer in both intrinsic and extrinsic apoptotic pathways, blocked acridine derivatives from inducing cell death. In addition, in vivo delivery of quinacrine and amsacrine induced p53 transcriptional activity in tumor xenografts. Our results reveal that DNA-intercalating acridine derivatives can induce p53 stabilization by a manner similar to CP-31398. These findings provide insights into p53 regulation in response to DNA intercalating drugs and may assist new anti-cancer drug design.