Copper-based chemical treatments are commonly used to eradicate invasive mussels in small ponds and lakes, but their use in large rivers has been limited. In 2023, in response to a detection of invasive quagga mussels, a 10-km reach of the Snake River (Idaho, USA), was treated with an unprecedented 19,300 kg of chelated copper molluscicide to a target concentration of 1,000 µg/L for 10 days. We assessed the transport and fate of the copper and its exposure and effects on the nontarget benthic community downstream. Water samples were collected at seven locations throughout the treatment period, and sediment, periphyton, and benthic macroinvertebrates were collected pre- and posttreatment. Nearly half of the original mass of copper was removed from the water column via sedimentation, sorption to algae, or biological uptake within the 10-km treatment reach and the first 15 km downstream. Even so, dissolved copper concentrations exceeded the acute toxicity threshold at least as far as 28 km downstream for more than 2 weeks. Sediment copper increased by up to 8.3-fold, exceeding the consensus-based sediment quality threshold effect concentration at several sites. Effects on benthic macroinvertebrates varied by taxa. From 0–28 km downstream, invertebrate abundances decreased 52%–94%, with gastropods among the most affected. Of the unique taxa present at these sites pretreatment, 52%–64% were not found posttreatment but were replaced by other taxa, indicating a reorganization of the base of the food web. Additionally, from 0–15 km downstream, the percentage of individuals from tolerant taxa increased two to15-fold. Findings from this study can help watershed managers plan future invasive mussel responses while protecting culturally, economically, and ecologically important nontarget species in large rivers.