Diabetes mellitus has reached epidemic levels, and it threatens the economy and health globally and Saudi Arabia in particular. The study assessed health-related quality of life using EuroQol instrument and its predictors among patients with Type 2 diabetes mellitus in Eastern Province, Saudi Arabia. A cross-sectional study was conducted among 378 patients with Type 2 diabetes mellitus from two major health centers in Eastern Province. The study showed moderate health-related quality of life, as reported by the median index score of 0.808 with more than a quarter of patients with severe-extreme health state in some or all domains. Multiple-regression models showed that male gender, high monthly income, having no diabetes-related complications and having random blood glucose level less than 200 mg/dl were prone to have a higher index score compared to the corresponding contrary groups. The study will help in guiding the development of effective intervention programs to improve diabetes-related health-related quality of life among the Saudi population.