This study applied machine learning (ML) algorithms to predict health-related quality of life (HRQOL) using comprehensive social determinants of health (SDOH) features. Data from the All of Us dataset, comprising participants with complete HRQOL and SDOH records, were analyzed. The primary outcome was HRQOL, which encompassed physical and mental health components, while SDOH features included social, educational, economic, environmental, and healthcare access factors. Three ML algorithms, namely logistic regression, XGBoost, and Random Forest, were tested. The models achieved accuracy ranges of 0.73-0.77 for HRQOL, 0.70-0.71 for physical health, and 0.72-0.77 for mental health, with corresponding area under the curve ranges of 0.81-0.84, 0.74-0.76, and 0.83-0.85, respectively. Emotional stability, activity management, spiritual beliefs, and comorbidity were identified as key predictors. These findings underscore the critical role of SDOH in predicting HRQOL and suggests future research to focus on applying such models to diverse patient populations and specific clinical conditions.