The present study authenticated for the first time that EGCG exhibited ameliorative properties against DNFB‐induced AD‐like skin lesions and comorbid anxiety and depression, and its reformative effects were likely partially mediated through the activation of the Keap1/Nrf2/HO‐1 signaling pathway, thereby relieving the excessive oxidative stress, altering the HPA axis dysfunction and upregulating the neurotransmitters. The gene discussed is KEAP1; the disease is major depressive disorder.