Periodontic-endodontic combined lesions affect the quality of life of patients. The present study aimed to explore a way to achieve maximal effect in treating periodontic-endodontic combined lesions by using a combination of minocycline hydrochloride ointment (MHO) and mineral trioxide aggregate (MTA). In the present study, 294 patients were randomly divided into four groups: Control group, MHO group, MTA group and combination group. Endodontic and periodontic therapy was applied simultaneously on the anterior and posterior teeth of patients, and patient characteristics, gingival index (GI) and probing depth (PD) were noted when the patients were treated with the different strategies. Reexamination was performed 4 weeks after treatment and follow-up was performed 2 years later. The present study demonstrated that medical history, root filling and periapical condition within the patients were deemed as key factors in determining the success of treatment of periodontic-endodontic combined lesions. The effect of the combination treatment significantly exceeded that of either treatment alone (P<0.05). In addition, the teeth were significantly improved for patients with pathological types I, II and III in the combination group compared with either treatment group alone (P<0.05). Furthermore, compared with the MTA and MHO groups alone, the combination group demonstrated a significant decrease in PD and GI in severe periodontic-endodontic combined lesions. In conclusion, the present findings implied that combination treatment is significantly superior to single treatments applied to patients with severe periodontic-endodontic combined lesions.