Globally, groundwater with high fluoride and arsenic receives extensive concern because of its wide distribution and great harm to human health caused by drinking water. In this paper, taking Tumochuan Plain in China as an example, based on hydrogeological investigation, groundwater flow system theory and hydro-chemical analysis methods were applied to reveal the mechanism of high fluoride and high arsenic in arid and semi-arid regions. In unconfined and confined groundwater of Tumochuan Plain, the highest concentration of fluoride is 7.2 and 11.2 mg/L respectively, and the highest concentration of total arsenic is 200.3 and 162.3 ?g/L respectively. Fluoride in groundwater is mainly derived from the soluble fluoride in soil and aquifer medium. Because of the water-rock interaction, the alkaline environment caused by the hydrolysis of feldspar minerals in the central part of the plain has an important influence on the accumulation of F and As in this area. High fluoride water is formed in the alkaline environment (high pH values) of high concentration of Na⁺ and low concentration of Ca²⁺. The high arsenic groundwater is distributed in the alkaline reducing environment that the content of soluble salt in aquifer media is high (>200 mg/100 g dry soil). The reductive dissolution of iron and manganese oxides and competitive adsorption of HCO₃^? all contribute to a high level of arsenic in both unconfined and confined aquifers. The research results have important guiding significance for water supply safety and water quality improvement in arid-semiarid areas in the world with high fluoride and high arsenic groundwater distribution.