The nasal epithelium houses a population of solitary chemosensory cells (SCCs). SCCs express bitter taste receptors and taste transduction signaling components and are innervated by peptidergic trigeminal polymodal nociceptive nerve fibers. Thus, nasal SCCs respond to bitter compounds, including bacterial metabolites, and these reactions evoke protective respiratory reflexes and innate immune and inflammatory responses. We tested whether SCCs are implicated in aversive behavior to specific inhaled nebulized irritants using a custom-built dual-chamber forced-choice device. The behavior of mice was recorded and analyzed for the time spent in each chamber. Wild-type (WT) mice exhibited an aversion to 10 mm denatonium benzoate (Den) or cycloheximide and spent more time in the control (saline) chamber. The SCC-pathway knock-out (KO) mice did not exhibit such an aversion response. The bitter avoidance behavior of WT mice was positively correlated with the concentration increase of Den and the number of exposures. Bitter-ageusic P2X2/3 double KO mice similarly showed an avoidance response to nebulized Den, excluding the taste system’s involvement and pointing to an SCC-mediated major contributor to the aversive response. Interestingly, SCC-pathway KO mice showed an attraction to higher Den concentrations; however, chemical ablation of the olfactory epithelium eliminated this attraction attributed to the smell of Den. These results demonstrate that activation of SCCs leads to a rapid aversive response to certain classes of irritants with olfaction, but not gustation, contributing to the avoidance behavior during subsequent irritant exposures. This SCC-mediated avoidance behavior represents an important defense mechanism against the inhalation of noxious chemicals.