The present study aimed to analyze local and regional changes in regards to odontogenic sinusitis in subjects with endo-periodontal lesions and diabetes mellitus and to investigate the effect on the level of glycemic control (glycated hemoglobin) that could be generated by adjunctive therapy with subantimicrobial doses of doxycycline. This study was performed on 51 subjects with diabetes who were divided into two therapeutic groups: 31 patients with diabetes (the study group) who underwent conventional endo-periodontal therapy and subantimicrobial doses of doxycycline and 20 patients with diabetes who followed only conventional endo-periodontal therapy (the control group). Patients underwent endodontic and periodontal clinical examination, with retro-dental-alveolar radiographs and CBCT examinations. For each patient, glycated hemoglobin A1c (HbA1c) was determined. This evaluation was performed at the beginning of the study, as well as 3, 6 and 12 months after baseline. A significant percentage of patients, both in the study group and in the control group, showed radiological signs of odontogenic sinusitis, totaling 29 patients (56.86%). Periodontal parameters revealed lower levels in patients who underwent the regimen which consisted of subantimicrobial doses of doxycycline; these results were maintained over the study period. Moreover, we demonstrated significantly reduced glycated hemoglobin levels throughout the study (12 months) in the doxycycline-treated group. This fact has far-reaching effects in the sphere of loco-regional complications as well, and the risk of odontogenic sinusitis can be significantly reduced.