AP-2 gamma (AP-2 gamma) is a transcription factor that plays pivotal roles in breast cancer biology. To search for small molecule inhibitors of AP-2 gamma, we performed a high-throughput fluorescence anisotropy screen and identified a polyoxometalate compound with Wells-Dawson structure K-6[P2Mo18O62] (Dawson-POM) that blocks the DNA-binding activity of AP-2 gamma. We showed that this blocking activity is due to the direct binding of Dawson-POM to AP-2 gamma. We also provided evidence to show that Dawson-POM decreases AP-2 gamma-dependent transcription similar to silencing the gene. Finally, we demonstrated that Dawson-POM contains anti-proliferative and pro-apoptotic effects in breast cancer cells. In summary, we identified the first small molecule inhibitor of AP-2 gamma and showed Dawson-POM-mediated inhibition of AP-2 gamma as a potential avenue for cancer therapy.