Abstract: Depression, a highly disabling psychiatric disorder, involves core disruptions in the epigenetic regulation (DNA methylation, histone modifications, non-coding RNA) of circadian clock genes (e.g., circadian locomotor output cycles kaput, brain and muscle ARNT-like protein 1, period, and cryptochrome). This dysregulation causes abnormal gene expression rhythms, leading to neurotransmitter imbalance, hypothalamic-pituitary-adrenal axis overactivation, and exacerbated neuroinflammation. We propose an "epigenetic-clock-neural circuit" interaction model, wherein suprachiasmatic nucleus master clock dysfunction disrupts synchronization of the hypothalamic-hippocampal-prefrontal circuit, constituting the core mechanism of emotional-cognitive comorbidity. Depression exhibits distinct circadian epigenetic signatures compared to epilepsy or dementia, revealing disease-specific mechanisms. Animal and clinical evidence converge on the pivotal role of circadian epigenetics. Diverse therapeutic strategies target this mechanism, including antidepressants, small-molecule inhibitors, behavioral interventions, gene editing/RNA therapies, and biomarker-guided personalized medicine. Treatment is evolving from generalized to personalized approaches, requiring novel targets and technologies. Despite challenges, this groundbreaking research opens new diagnostic and therapeutic avenues, advancing psychiatry into an era of "circadian medicine".