Fertilization affects soil processes in many ways that remain unclear. The effects of N, P, and K application on plant growth and Cu and Pb accumulation were thus evaluated in a soil-maize system using five treatments: N, P, and K application; N and P application; N and K application; P and K application; and control (no fertilization). Compared to the control, fertilizer application treatments, especially N application, significantly increased maize photosynthetic rate, which further improved shoot biomass production. Root growth, root and shoot Cu and Pb concentrations, and Cu and Pb mobility also significantly altered with fertilizer application. Shoot Cu contents, root Cu uptake and translocation factors were significantly increased in the N-fertilized treatments. The significant decrease of shoot Pb concentration and root Pb uptake and increase of Cu and Pb immobilization were observed in the P-fertilized treatments. No significant correlation was observed between K application and Cu and Pb accumulation in maize. Our results show that an increase in P application and decrease in N application is recommended to reduce agro-ecological risks associated with Cu and Pb in soil-maize systems. However, the mechanisms governing the relationship between nutrients and heavy metal transformation in soil-plant systems needs further research.