While the hyporheic zone (HZ) accounts for a significant portion of whole stream CO2 concentrations, HZ respiration modeling studies are lacking in quantifying their contributions to the total CO2 at large watershed/basin scales. Quantifying the contribution of anaerobic respiration is also underappreciated. This study used a carbon-nitrogen-coupled river corridor model to quantify HZ aerobic and anaerobic respiration and determined the key factors controlling their spatial variability within the Columbia River Basin (CRB). The modeled respiration patterns showed high spatial variability. Among the nine sub-basins composing the CRB, the Lower Columbia and the Willamette, which receive higher precipitation, had higher respiration. Medium-sized rivers (fourth to sixth orders) produced the highest aerobic and anaerobic respiration among reaches of different sizes. At the basin scale, aerobic respiration is dominant, representing approximately 98.7% of the total respiration across the CRB. While most of the reaches were dominant with aerobic respiration, reaches in agricultural land showed a relatively higher anaerobic respiration (18%) ratio. A variable importance analysis showed that hyporheic exchange flux controlled most of the spatial variability of HZ respiration, dominating over other physical variables such as residence time, stream dissolved organic carbon (DOC), nitrate, and dissolved oxygen (DO). The influence of substrate concentration (DOC and DO) is larger in modeling anaerobic respiration than aerobic respiration. Future efforts will focus on improving the estimation of the HZ exchange flux and the implementation of spatially explicit parameterizations for the reactions of interest to reduce model uncertainty.