Background: As healthy diet and physical activity can improve glucometabolic control in patients with type 2 diabetes, lifestyle changes should be the basis for each therapy. The only tool to visualize immediate effects of food pattern and exercise on blood glucose levels is self-monitoring of blood glucose (SMBG). Therefore, the aim of the 12-week lifestyle intervention ROSSO-in-praxi was to evaluate the impact of an SMBG-structured motivation and education program on glucometabolic and health parameters in diabetes patients not treated with insulin. Methods: Participants (n = 405) generated a seven-point blood glucose diurnal profile every 4 weeks, including actual weight, waist circumference, and steps/day. At baseline and the end of the study, glycated hemoglobin A1c (HbA1c), blood pressure, and cholesterol levels, lifestyle changes, and well-being (SF36 and Center for Epidemiologic Studies Depression Scale questionnaires) were assessed. Results: Three hundred twenty-seven participants (81%) completed the program and significantly improved quality of diet and physical activity, accompanied by an increase of >2,300 steps/day. Participants significantly reduced weight, body mass index, waist circumference, blood glucose, blood pressure, low-density lipoprotein cholesterol, and HbA1c by 0.3% (all P < 0.001), accompanied by increased physical and mental health and reduced depression measurements. Weight loss was significantly associated with overall improvements of glucometabolic and health parameters and mean reduction of 0.05% HbA1c/kg. Conclusions: The evaluated SMBG-structured lifestyle intervention is applicable to motivate individuals with type 2 diabetes for lifestyle changes. Integration of this short-term, highly motivational, and low-cost intervention into basic therapy for patients without insulin therapy could strengthen patient empowerment in order to change lifestyle and to improve glucometabolic and general health.