Background: Oxidative stress triggered by hyperglycemia in diabetic patients leads to macrovascular and microvascular complications, resulting in deterioration in the quality of life. Aims: This study aimed to compare the oxidative stress status and quality of life in participants with type 2 diabetes mellitus according to treatment modality. Patients and Methods: Ninety type 2 diabetes mellitus participants aged between 40 and 60 years were included in the study. Forty-five participants were receiving oral antidiabetic drugs and 45 participants were receiving insulin therapy. Total antioxidant status, total oxidant status, and paraoxonase-1 were measured and oxidative stress indices were calculated. The SF-36 quality of life questionnaire was applied to the participants. Results: The total oxidant status and oxidative stress indices values were higher in the insulin-treated group than in the group treated with oral antidiabetic drugs. Paraoxonase-1 activities of the oral antidiabetic drugs-treated group were statistically significantly higher than the insulin-treated group. In the oral antidiabetic drugs-treated group, the physical function, social function, and pain subscale scores were higher than that of the insulin-treated group. In all participants, a negative correlation between total antioxidant status and fasting blood glucose and hemoglobin A1c, a positive correlation between total oxidant status and hemoglobin A1c and triglyceride, and a positive correlation was found between oxidative stress indices and fasting blood glucose and hemoglobin A1c. Conclusions: It was found that oxidative stress parameters were higher and quality of life was worse in the insulin-treated participants than participants treated with oral antidiabetic drugs. These results may be closely related to more severe chronic complications in insulin-dependent diabetes.