Background: Health-Related Quality Of Life (HRQOL) is an important consideration for persons with Chronic Obstructive Pulmonary Disease (COPD). This convergent parallel mixed-methods study aimed to examine the factors predicting HRQOL and to explore a comprehensive in-depth understanding of the factors associated with HRQOL in persons with COPD. Methods: For the quantitative arm, simple random sampling consisted of 240 persons with COPD in Public Health Region 4, Thailand and self-reported questionnaires were employed and analyzed by using SPSS version 22.0 software. For the qualitative arm, purposive sampling consisted of 30 participants that were interviewed and the transcripts analyzed using content analysis. Subsequently, a side-by-side joint display table was used to merge the data. Results: Social support was the strongest predictor of HRQOL, followed by nutritional status, pulmonary function, and functional performance with R2 = 0.801, p = 0.00. The participants perceived that social support can create encouragement, build convenience, and offer good recommendations. They also reported that the effects of COPD included poor nutritional status, deteriorating lung function, and activity limitations resulting in inadequate self-care in people living with COPD. Although age and gender were not found to be significant predictors of HRQOL, the participants perceived that differences in age and gender did not predict the prognosis of the disease. Conclusion: Four factors were seen to be significant predictors of HRQOL and potential explanations for the identification of the factors predicting HRQOL. Nurses and healthcare teams can modify the predicting factors and implement appropriate care leading to increased HRQOL in persons with COPD.