Since the urbanization and industrialization are wildly spread in recent decades, the concentration of Zn in soil has increased in various regions. Although the interactions between P and Zn has long been recognized, the effect of high level of Zn on P uptake, translocation and distribution in rice and its molecular mechanism are not fully understood. In this study, we conducted both hydroponic culture and field trial with different combined applications of P and Zn to analyze the rice growth and yield, the uptake, translocation and distribution of P and Zn, as well as the P- and Zn-related gene expression levels. Our results showed that high level of Zn decreased the rice biomass and yield production, and inhibited the root-to-shoot translocation and distribution of P into new leaves by down-regulating P transporter genes OsPT2 and OsPT8 in shoot, which was controlled by OsPHR2-OsmiR399-OsPHO2 module. High Zn supply triggered P starvation signal in root, thereafter increased the activities of both root-endogenous and -secreted acid phosphatase to release more Pi, and induced the expression OsPT2 and OsPT8 to uptake more P for plant growth. On the other hand, high level of P significantly decreased the Zn concentrations in both root and shoot, and the root uptake ability of Zn through altering the expression levels of OsZIPs, which were further confirmed by the P high-accumulated mutant osnla1-2 and OsPHR2-OE transgenic plant. Taken together, we revealed the physiological and molecular mechanisms of P-Zn interactions, and proposed a working model of the cross-talk between P and Zn in rice plants. Our results also indicated that appropriate application of P fertilizer is an effective strategy to reduce rice uptake of excessive Zn when grown in Zn-contaminated soil.