Removing arsenic (As) from drinking water is widely dependent on iron (Fe)-based coagulation/flocculation techniques. However, little is known about the influence of Fe precipitant on As toxicity. In this present study, the influence of Fe on As toxicity was determined at systems biology level by in vitro and in vivo experiments. In vitro study based on HepG2 cell line found that Fe increased the As toxicity on cell viability and DNA damage, indicating the synergetic toxic effects. However, when the Fe and As were simultaneously exposed to mice by drinking water for 90 days, the results showed that Fe reduced the changes of hepatic transcriptomic profiles and serum and urine metabolic profiles caused by As exposure, showing the antagonistic toxic effects. The antagonistic effects might be because Fe reduced As bioavailability and accumulation, which was verified by As and Fe levels in feces and liver. The results of this study indicate that Fe precipitant can influence the As toxicity. The interactions between As and Fe and their bioavailability might play important roles in the As toxicity. When assessing the safety of As in drinking water, it is necessary to fully consider the combined effects of As and Fe.