Objective To explore the effect of root canal therapy combined with guided tissue regeneration (GTR) in the treatment of patients with combined periodontal-endodontic lesions. Methods A total of 90 patients with combined periodontal-endodontic lesions admitted to our hospital from December 2024 to December 2025 were selected, and they were divided into the control group and the observation group by the random number table method, with 45 patients in each group. The control group received traditional periapical surgery, and the observation group received root canal therapy combined with GTR. The clinical efffcacy, periodontal indicators, imaging evaluation indicators and inflammatory factor levels were compared between the two groups. Results The total effective rate of the observation group was 95.56%, which was higher than 77.78% of the control group (P<0.05). After treatment, thePLI, GBI, PD and tooth mobility of the observation group were lower than those of the control group, and the occlusal force was higher than that of the control group (P<0.05). The periapical lesion healing score of the observation group after treatment was lower than that of the control group, and the alveolar bone density and new bone formation thickness were higher than those of the control group (P<0.05). The levels of IL-1β, TNF-α and hs-CRP in the observation group after treatment were lower than those in the control group (P<0.05). Conclusion The application of root canal therapy combined with GTR in patients with combined periodontal-endodontic lesions can improve the treatment effect, optimize periodontal indicators, promote the healing of periapical lesions, increase alveolar bone density and new bone formation, and help to reduce local inffammatory levels, which has good clinical application value.