Due to a lack of toxicity reference values that match the regional environmental characteristics, the ecological risk of metals in water bodies cannot be accurately assessed. The Fen River is the second-largest tributary of the Yellow River in China, and the sustainability of this area is threatened by heavy metal pollution caused by intensive industrial and agricultural activities. In this study, site-specific water quality criteria (WQCs) for heavy metals in the Fen River were derived considering toxicity data from native aquatic organisms and regional water quality factors (e.g., water hardness). Short-term WQCs for Mn, Cu, Cd, Zn, Cr, Pb, and Ni were 2026.15, 98.62, 10.02, 63.07, 6.06, 166.74, and 132.73 μg/L, respectively, and long-term WQCs were 166.53, 29.71, 2.18, 19.29, 4.15, 6.38, and 14.76 μg/L, respectively. The distribution characteristics of these metals during the wet season in 2020 were explored, and their average concentrations in the river water did not exceed the environmental quality standards for surface water in China but were higher than the world average levels. Cr was the main pollutant in the sampling sites of Yaodu region, Hongdong Shitan, Xiao River, and Duanchun River, as was Pb in Duanchun River. Based on the site-specific WQCs, using hazardous quotient (HQ) and margin of safety (MOS10) approaches, a high risk of Pb was identified in the Duanchun River, and a medium risk of Cr might occur at midstream and downstream of Yaodu and Xiaodian. The results will provide a reference basis for heavy metal pollution control and water quality management in the Fen River.