Chronic pain and depression are two common diseases that seriously affect the physical and mental health of patients. Clinical observations and animal studies have shown a high comorbidity rate between these two diseases, which exacerbates the developing course of each disease. Recent research on the central regulatory mechanisms of chronic pain and depression has made notable progress, uncovering overlaps and interactions in the regulating brain regions, biological pathways, and neurotransmitters. This review aims to summarize current preclinical studies on chronic pain and depression, outline existing animal models and detection methods for pain‑depression comorbidity, and highlight the central regulatory mechanisms underlying their interaction. By integrating these researches, This review aims to provide a comprehensive theoretical foundation for understanding the comorbidity mechanism of chronic pain and depression, thereby facilitating the development of more effective treatment strategies.