The homeodomain-leucine zipper (HD-ZIP) is a plant-specific transcription factor family that plays important roles in plant developmental processes in response to multiple stressors. We previously isolated a cotton HD-ZIP class I transcription factor gene, GhHB12, which is regulated by the circadian clock and photoperiodism. Furthermore, it regulates cotton architecture, phase transition, and photoperiod sensitivity. Here we report that GhHB12 was induced by methyl jasmonate (MeJA) and Verticillium dahliae infection. Additionally, stress-responsive elements were found in the GhHB12 promoter. Promoter fusion analysis showed that GhHB12 was predominantly expressed in primary roots and that it was induced by mechanical damage. Overexpression of GhHB12 increased susceptibility of the cotton plant to the fungal pathogens Botrytis cinerea and V. dahliae, which was coupled with suppression of the jasmonic acid (JA)-response genes GhJAZ2 and GhPR3. Our results suggest that GhHB12, a cotton stress-responsive HD-ZIP I transcription factor, negatively regulates cotton resistance to V. dahliae by suppressing JA-response genes.