As the largest tributary of the Yellow River, the Wei River drains a basin mainly comprising two different geological settings, i.e., the Chinese Loess Plateau (CLP) in the north covered by Quaternary loess and the Qinling Mountains area in the south. Exploring the influence of natural weathering processes and human activities on river chemistry has high significance in understanding chemical transport from the Wei River to the Yellow River. The geochemical characteristics of the Wei River mainstream and its tributaries as well as chemical weathering were determined using a geochemistry and isotope dataset of high spatial resolution. The mainstream clearly exhibited a mixture of major elements and stable isotopes from tributaries on both the north and south banks, with values within the range of those of the tributaries. North-bank tributaries draining thick loess deposits showed higher contents of major elements and the enrichment of stable isotopes, reflecting the influence of geological setting on river chemistry. The dominant processes accounting for the water chemistry of the mainstream are evaporite (39–75%) and carbonate weathering (21–54%). Within the watershed, evaporite dissolution and silicate weathering are higher in the northern CLP area, whereas carbonate weathering is higher in the southern Qinling Mountain area. The CO₂ consumption by the Wei River is 19.9 × 10⁹ mol/yr, accounting for 32.5% of the total CO₂ consumption by the middle reaches of the Yellow River. During the high-flow period, the chemical weathering flux of the Wei River was found to be within the range of northern rivers in China, while the chemical weathering rate was relatively high in the semi-arid region. This suggests that chemical denudation is a significant factor for the river chemistry of the CLP at least in the high-flow period.