The ideal lifestyle intervention to battle both obesity and diabetes is currently unknown. The aim of this pilot uncontrolled intervention trial was to assess the effect of a modified Mediterranean diet (MedDiet) on weight loss and glucoregulation among overweight/obese adults. Eleven men and women with overweight/obesity, aged 37 ± 12 years, participated in a free-living intervention until 10% weight loss was achieved. Participants followed an individualized MedDiet high in monounsaturated fat and protein with decreased carbohydrate and saturated fat contents. Physical activity and dietary intake were monitored with pedometers and food records, respectively. Upon weight loss achievement, anthropometric measurements, blood metabolic profiles and individual responses to oral glucose and mixed-meal tests were evaluated pre- and post-intervention. The results showed significant ameliorations in body fat, waist circumference and leptin levels (p < 0.01), with concomitant increases in adiponectin–leptin ratios (p < 0.001). Glucoregulation was significantly improved according to glucose and insulin responses, homeostatic model assessment of insulin resistance indices and postprandial insulin sensitivity indices (p < 0.05). In conclusion, the modified Mediterranean diet may induce significant improvements in body composition, adipocytokine profile and glucose metabolism in overweight/obese individuals. Notably, ameliorated glycemia and increased insulin sensitivity may be retained even at postprandial level, irrespective of the meal consumed.