To investigate the associations of job-related psychological flexibility, coping style and personality types with and their interactions in depression in Chinese physicians. A cross-sectional survey of 444 physicians was conducted by using the convenience sampling method in the municipal hospitals in Zhengzhou, Henan province. Center for Epidemiological Studies Depression, Work-related Acceptance and Action Questionnaire, the Simplified Coping Style Questionnaire and Eysenck Personality Questionnaire-Revision Short Scale of China were administered to each participant. Depression tendency scores were significantly higher in healthcare workers with intermediate title, age 31 and older, introvert unstable personality than other counterparts, (P < .01). Female and extrovert stable healthcare workers had significantly higher coping score than male and other personality types (P < .05). The scores of job-related psychological flexibility in healthcare workers with Introvert Stable or working in emergency department were significantly higher than their counterparts (P < .01). General linear model algorithm of machine learning showed that Extrovert Unstable was the main risk factor for depression (β = 6.74), followed by Extrovert Stable (β = −4.90), negative coping, positive coping, and length of service. Multivariate regression models showed that a significant interaction existed between coping style, work-related psychological flexibility and Extroversion (β = −0.103, P < .05), independently explaining 0.7% variance of depression, and that a significant interaction existed between coping style, work-related psychological flexibility and neuroticism (β = 0.116, P < .05), independently explaining 1.0% variance of depression. Interactions existed between personality types, coping style and work-related psychological flexibility in depression tendency in Chinese healthcare workers, with neuroticism (extrovert unstable) being a risk factor and extroversion (extrovert stable) being a protective factor. Precision prevention strategies could be made based on personality types to reduce depression in health workers.