Elevated concentrations of CO₂ in seawater can disrupt numerous sensory systems in marine fish. This is of particular concern for Pacific salmon because they rely on olfaction during all aspects of their life including during their homing migrations from the ocean back to their natal streams. We investigated the effects of elevated seawater CO₂ on coho salmon (Oncorhynchus kisutch) olfactory-mediated behavior, neural signaling, and gene expression within the peripheral and central olfactory system. Ocean-phase coho salmon were exposed to three levels of CO₂, ranging from those currently found in ambient marine water to projected future levels. Juvenile coho salmon exposed to elevated CO₂ levels for 2 weeks no longer avoided a skin extract odor that elicited avoidance responses in coho salmon maintained in ambient CO₂ seawater. Exposure to these elevated CO₂ levels did not alter odor signaling in the olfactory epithelium, but did induce significant changes in signaling within the olfactory bulb. RNA-Seq analysis of olfactory tissues revealed extensive disruption in expression of genes involved in neuronal signaling within the olfactory bulb of salmon exposed to elevated CO₂, with lesser impacts on gene expression in the olfactory rosettes. The disruption in olfactory bulb gene pathways included genes associated with GABA signaling and maintenance of ion balance within bulbar neurons. Our results indicate that ocean-phase coho salmon exposed to elevated CO₂ can experience significant behavioral impairments likely driven by alteration in higher-order neural signal processing within the olfactory bulb. Our study demonstrates that anadromous fish such as salmon may share a sensitivity to rising CO₂ levels with obligate marine species suggesting a more wide-scale ecological impact of ocean acidification.