Chronic atopic dermatitis (AD) affects millions globally and has an alarming propensity to generate comorbid chronic depression. Currently, no effective therapies exist specifically for AD-generated comorbid depression (ADCD), likely due to unknown itch- and affect-processing brain mechanisms and inadequate preclinical models. Hence, there is a critical need for a suitable pre-clinical research model that can be used to study ADCD’s unique pathophysiology. In this investigation, we searched for preclinical models of ADCD by evaluating previously established house dust mite-induced (HDM model) and MC903-induced (MC903 model) AD mouse models for comorbid depression-like features. Using the elevated plus maze, forced swim test, scratching behavior assays, histology, and clinical skin scoring, we show that the HDM model lacks significant anxiety-like (p = 0.858, student’s t-test) and depression-like behavior (p = 0.0512), but develops an AD-like skin pathology with strong scratching behavior (p < 0.005). By contrast, the MC903 model uniquely displays not only a more robust AD-like skin pathology, but also concomitantly significant scratching bouts (p < 0.0001), scratching duration, (p = 0.047), anxiety-like (p = 0.0367) and depression-like (p = 0.0256) behavior, and a greater state of stress (p < 0.005) indicated by serum corticosterone ELISA. Ultimately, our investigation reveals that both models faithfully recapitulate human AD pathology features, but only the MC903 model generated concomitant ADCD-like features. Using the MC903 model, future investigations will explore itch- and affect-processing brain regions for structural and functional hallmarks of the depression-like state and identify potential circuit-based therapeutic targets for treating this comorbidity.