The present study evaluates the sustainability of tobacco-rice rotation by reducing the phytoavailability of cadmium (Cd) to rice by combining large-scale field sampling and regional investigations in southern China. The rotation involves frequent tillage and liberal application of nitrogen and phosphorus fertilizers, which increases yields but lowers soil pH. As a result, manganese is lost from soil and, at the same time, more soil Cd is taken up by rice and tobacco. The tendency to overcompensate for the Mn loss is influenced by soil properties, crop type, and economics of cultivation. Based on the scenario analysis, this tendency and the Cd uptake risks were estimated. Dietary intake of 83.3% of rice grain produced on the rotation fields would have adverse health effects on local male nonsmokers. Besides the rice, Cd in local tobacco leaf may lead to an increase in the kidney Cd levels of local male smokers (21.5 cigarettes per day) by 16.2-fold at age 50. Field trials and model estimations indicated that for a Cd concentration below 0.2 mg dry weight kg-1 in rice grain, the critical pH value in rice soils was ~ 6.0, and that for amorphous Mn oxide at pH 4.5–6.0 was 120 mg kg−1.