Allergen-specific IgE multiplex serology enables the molecular characterization of sensitizations in large populations. This study analyzed results from 21,121 canine sera collected in the USA during 2024–2025 using the Pet Allergy Xplorer (PAX) 238-allergen platform to determine sensitization prevalence and profiles. Sensitization to at least one allergen and to at least one environmental allergen was detected in 90.7% and 86.2% of dogs, respectively. House dust mites (HDM) were the predominant allergens (79.5%), followed by Hymenoptera venoms (39.8%), meats (21.9%), weeds (21.5%), and tree pollens (18.6%). Sensitization to the Dermatophagoides farinae HDM was the most prevalent (76.7%). Unsupervised clustering of 16,366 sensitized dogs identified six biologically coherent profiles centered on flea saliva, mammalian serum albumins/IgGs, honeybee venom, HDM group-2 allergens, storage mites, and PR-10-family allergens. A second, pollen/plant-food-focused analysis found clusters associated with Parietaria Par j 2, ragweed, granule-bound starch synthases, and PR-10 allergens, as well as a minor Phl p 6-associated grass pollen profile. Altogether, these results define the molecular sensitization repertoire of allergic dogs in the US and provide the background for interpreting IgE serological results and optimizing allergen selection for immunotherapy.