Aim and objectives To identify physiological, psychological and socioenvironmental factors that affect the health‐related quality of life of Thai men living with chronic obstructive pulmonary disease. The vast majority of Thai persons living with chronic obstructive pulmonary disease are men. Background Little is known about the health‐related quality of life of Thai people living with chronic obstructive pulmonary disease or about the physiological and psychosocial factors that most affect it. Applying a prevailing theoretical model of health‐related quality of life, we explored how physiological, psychological and socioenvironmental factors simultaneously affect the health‐related quality of life of Thai men with chronic obstructive pulmonary disease. Design A cross‐sectional study design was used, together with the STROBE checklist. Methods In this study, 290 Thai male outpatients at a chronic obstructive pulmonary disease specialist clinic near Bangkok were recruited using purposive sampling. The participants completed the Satisfaction With Life Scale, the St. George Respiratory Questionnaire, the Center for Epidemiologic Studies Depression Scale, the Short Form Health Survey Version 2, the chronic obstructive pulmonary disease Self‐Efficacy Scale and the Social Support Questionnaire. A structural equation model was used to examine the relationships between the assessed variables. Results Biological function (FEV‐1, chronic obstructive pulmonary disease exacerbations), symptoms (chronic obstructive pulmonary disease and depression), functional status, general health perceptions and individual characteristics (age and self‐efficacy to control dyspnoea) accounted for 56.9% of the variance in health‐related quality of life. Conclusions Symptoms of chronic obstructive pulmonary disease and depression were the main factors with statistically significant direct and indirect effects on the health‐related quality of life of the Thai men in this study. The effects of both symptoms included an indirect effect on health‐related quality of life through functional status and general health perceptions. Relevance to clinical practice The study findings may help nurses to better understand factors affecting health‐related quality of life among men with chronic obstructive pulmonary disease. Preventing or minimising symptom exacerbations could be important in nursing practice. Cognitive‐behavioural interventions addressing chronic obstructive pulmonary disease symptom management, depression screening and smoking cessation may improve health‐related quality of life among Thai men with chronic obstructive pulmonary disease.