Upregulation of Cancerous Inhibitor of PP2A (CIP2A) plays an important role in disease- related phosphorylation of tau/APP and tau pathology/Aβ overproduction through inhibiting PP2A in AD brain. Genistein has been shown to potently reduce CIP2A in experimental cancer treatment research. In this study, the inhibitory effect of Genistein on tau/APP phosphorylation and Aβ overproduction in AD cell models have been explored. The results showed that Genistein effectively reduced CIP2A expression, and restored PP2A activities both in CIP2A/APP and CIP2A/tau co-expressed cells. Genistein reduced APP phosphorylation at T668 site and inhibited Aβ production. In the meantime, Genistein ameliorated tau hyperphosphorylation by repressing the inhibitory effect of CIP2A on PP2A. Thus, Genistein has the potential to be used in AD treatment by targeting CIP2A-PP2A signaling in AD therapy.