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Background: Obesity is the main cause of insulin resistance and type 2 diabetes mellitus (T2DM). Diet therapy is the cornerstone in the management of obesity and T2DM. Objectives: We evaluated the effects of calorie-restricted diet therapy on the circulating level of the serum lipid profile, glucose, insulin, and adiponectin in obese women with T2DM. Materials and Methods: This randomized clinical controlled trial was performed for 10 weeks on 30 eligible obese T2DM women distributed to control (n = 15) and diet therapy (n = 15) groups. Demographic, nutritional, anthropometric, and laboratory data were obtained before and after the study. Data were analyzed by SPSS vs.15 and Nutritionist IV. Results: In addition to anthropometric measurements, diet therapy independently improved fasting blood sugar (P = 0.024, -69.37 to -5.57 mg/dL), 2-h postprandial blood sugar (P = 0.007, -123.34 to -22.3 mg/dL), serum total cholesterol (P = 0.005, -46.48 to -9.72 mg/dL), serum alanine transaminase (P = 0.001, -8.91 to -3.18 U/L), and increased circulating adiponectin (P = 0.038, 0.01 to 0.47 μg/mL). Conclusions: Improvement of biomarkers of insulin sensitivity, including adiponectin and lipid metabolism, is an important therapeutic effect of medical nutrition therapy in obese patients with T2DM.