Arsenic (As) and lead (Pb) commonly co-exist with high concentrations in paddy soil mainly due to human activities in south of China. This study investigates the effect of ferrous sulfate (FeSO4) amendment and water management on rice growth and arsenic (As) and lead (Pb) accumulation in rice plants. A paddy soil co-contaminated with As and Pb was chosen for the pot experiment with three FeSO4 levels (0, 0.25, and 1%, on a dry weight basis) and two water managements (flooded, non-flooded). The concentrations of As and Pb in iron plaques and rice plants were determined. Application of FeSO4 and non-flooded conditions significantly accelerated the growth of rice plants. With the addition of FeSO4, iron plaques were significantly promoted and most of the As and Pb were sequestered in the iron plaques. The addition of 0.25% FeSO4 and non-flooded conditions did not significantly change the accumulation of As and Pb in rice grains. The practice also significantly decreased the translocation factor (TF) of As and Pb from roots to above-ground parts which might have been aided by the reduction of As and Pb availability in soil, the preventing effect of rice roots, and the formation of more reduced glutathione (GSH). Flooded conditions decreased the Pb concentration in rice plants, but increased As accumulation. Moreover, rice grew thin and weak and even died under flooded conditions. Overall, an appropriate FeSO4 dose and non-flooded conditions might be feasible for rice cultivation, especially addressing the As issue in the co-contaminated soil. However, further detailed studies to decrease the accumulation of Pb in edible parts and the field application in As and Pb co-contaminated soil are recommended.