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The relative capacity for watersheds to eliminate or export reactive constituents has important implications on aquatic ecosystem ecology and biogeochemistry. Removal efficiency depends on factors that affect either the reactivity or advection of a constituent within river networks. Here, we characterized Damköhler number (Da) for dissolved organic carbon (DOC) uptake in global river networks. Da equals the advection to reaction timescale ratio and thus provides a unitless indicator for DOC reaction intensity during transport within river networks. We aim to demonstrate the spatial and temporal patterns and interplays among factors that determine DOC uptake across global river networks. We show that watershed size imposes a primary control on river network DOC uptake due to a three orders of magnitude difference in water residence time (WRT) between the smallest and largest river networks. DOC uptake capacity in tropical river networks is 2–6 times that in temperate and the Arctic river networks, coinciding with larger DOC removals in warm than in cold watersheds. River damming has a profound impact on DOC uptake due to significantly extended WRTs, particularly in temperate watersheds where most constructed dams are situated. Global warming is projected to increase river network DOC uptake by ca. 19% until year 2100 under the RCP4.5 scenario.