In the present study, we quantified the 4-h uptake and 48-h toxicity of Cd and Zn in a freshwater cyanobacterium, Microcystis aeruginosa, under varied cellular and ambient P concentrations. After acclimation under different P conditions, the cyanobacteria had different cellular P concentrations. We found that an elevated cellular P concentration significantly promoted the short-term uptake of Cd and Zn by M. aeruginosa. With an increase in the cellular P concentration from 66 to 118 micromol/g, the uptake rates of Cd and Zn increased by 40- and 16-fold, respectively, and a significant exponential relationship between metal uptake rate and cellular P concentration was observed. The pulse amplitude-modulated parameter (maximum photosystem II quantum yield) and cell-specific growth rate were used as toxicity endpoints of cyanobacteria over 48 h of metal exposure. The P-replete cells were more tolerant of [Cd2+] or [Zn2+] than the P-starved cells but became more sensitive to Cd toxicity when incubated in a P-deficient medium. The polyphosphate bodies may have formed in the cyanobacterial cells under surplus P conditions, which can serve as a metal sink to sequester/detoxify the incoming Cd and Zn. The geometric means of median inhibition concentration based on the cellular metal to P ratio (mol:mol) were 0.041 and 0.036 for Cd and Zn, respectively. The cellular metal to P ratio was better than the cellular P concentration at predicting the toxic effects of metals under different P conditions.