Despite the significance of river leakage to riparian ecosystems in arid/semi-arid regions, a true understanding and the accurate quantification of the leakage processes of ephemeral rivers in these regions remain elusive. In this study, the patterns of river infiltration and the associated controlling factors in an approximately 150-km section of the Donghe River (lower Heihe River, China) were revealed using a combination of field investigations and modelling techniques. The results showed that from 21 April 2010 to 7 September 2012, river water leakage accounted for 33% of the total river runoff in the simulated segments. A sensitivity analysis showed that the simulated infiltration rates were most sensitive to the aquifer hydraulic conductivity and the maximum evapotranspiration (ET) rate. However, the river leakage rate, i.e., the ratio of the leakage volume to the total runoff volume, of a single runoff event relies heavily on the total runoff volume and river flow rate. In addition to the hydraulic parameters of riverbeds, the characteristics of ET parameters are equally important for quantifying the flux exchange between arid ephemeral streams and underlying aquifers. Coupled surface/groundwater models, which aim to estimate river leakage, should consider riparian zones because these areas play a dominant role in the formation of leakage from the river for recharging via ET. The results of this paper can be used as a reference for water resource planning and management in regulated river basins to help maintain riparian ecosystems in arid regions.