Paddy soils in southern China are heavily co-polluted by arsenic (As) and cadmium (Cd). The accumulation of these contaminants in rice grains may pose a high health risk. We evaluated the impact of adjusted water management practice (i.e., conventional irrigation and aerobic treatment after heading stage) and the application of two immobilization agents (i.e., CaO and Fe2O3) on the accumulation of As and Cd in rice grains of three rice varieties (i.e., Jinyou-463, Jinyou-268, and Mabayouzhan). The different schemes were tested via conducting a field experiment in paddy soil in Shaoguan, Guangdong Province, China. The results showed that the combined scheme (selecting Jinyou-268, aerobic water management after the heading stage, and 0.09% CaO and 0.5% Fe2O3 amendments) exhibited the best performance in the reduction of As and Cd accumulation in rice grains. This combined scheme decreased the grain As concentration by 26.19% and maintained the Cd at a low level (0.056 mg/kg) as compared to the use of local conventional irrigation patterns. Moreover, health risk assessment demonstrated that by applying the optimal scheme, neither As nor Cd content in rice had carcinogenic risk. However, the grain As remains at a high non-carcinogenic risk. We suggest that future field study design should fully incorporate the uncertainty of the natural environment to make the research conclusions more feasible for popularization and utilization. This study demonstrated an approach of utilizing the synergy effects of various measures for safe rice production in fields subjected to As and Cd contaminations.