Abstract：This article introduces Professor ZHOU Hong's clinical experience in treating depression and insomnia by three-differentiation model. Professor ZHOU proposes a model that prioritizes disease differentiation， constitution differentiation， and syndrome differentiation. In terms of disease differentiation， it is believed that the fundamental pathogenesis of depression and insomnia lies in the disharmony between yin and yang，excess of moodiness，and deficiency of qi and blood. For constitution differentiation， patients with depression and insomnia are mainly categorized into constitution of qi constraint and yang deficiency， with some also exhibiting constitution of blood stasis and qi deficiency. Syndrome differentiation focuses on five primary symptoms (emotional state，sleep state，oral sensations， aversion to cold and heat， pulse diagnosis) and four secondary symptoms (stool status， appetite， condition of the lower back and knees， sweating). By flexibly applying methods to harmonize the exterior and interior，yin and yang，cold and heat，and qi and blood，clinical outcomes are often favorable.