In spring 2019, the Oklahoma segment of the McClellan-Kerr Arkansas River Navigation System (OK-MKARNS), a significant in-land water transportation segment in the Central Great Plains region of the United States, was forced to close for months due to an extreme flooding event. The OK-MKARNS supports the economy of multiple states and their connection to domestic and international markets through the Mississippi River. However, the flood’s direct, indirect, and induced impacts on Oklahoma’s economy and the economies of the surrounding states of Arkansas, Colorado, and Kansas are unknown. The disruption’s impacts on the region’s economies are evaluated at the congressional district levels of these states using a multi-regional input–output model. Disruption of the waterway transportation resulted in a total loss ranging between 66 and 791 jobs, $15.36 to $175.04 million in output, and $6.08 to $72.98 million in value-added, depending on the duration of the delay experienced by industries. The magnitude of economic loss varied for each congressional district, depending on its economic base’s composition and proximity to the OK-MKARNS navigational system. These findings could be helpful to legislators and other decision-makers in allocating scarce resources toward the maintenance of navigable waterway infrastructure. The multi-regional focus of the analysis also suggests a potential role concerning collaborative efforts between legislators across state borders to garner federal spending to support navigable waterway services.