Objective To explore the effect of microscopic root canal therapy combined with periodontal tissue regeneration on periodontal indicators in patients with endodontic-periodontal lesions (EPL). Methods A total of 86 patients with EPL admitted to Suzhou Stomatological Hospital from January 2022 to December 2025 were selected as the research subjects. According to the random number table method, they were divided into group A and group B, with 43 patients in each group. Group A received microscopic root canal therapy alone, and group B received microscopic root canal therapy combined with periodontal tissue regeneration. The clinical efficacy, periodontal indicators, inflammatory indicators and Oral Health Impact Profile-14 (OHIP-14) score were compared between the two groups. Results The total effective rate of group B (97.67%) was higher than that of group A (81.40%) (P<0.05). At 3 months after treatment, the PD, AL, SBI and PLI in group B were lower than those in group A (P<0.05). At 3 months after treatment, the levels of hs-CRP and IL-1β in group B were lower than those in group A (P<0.05). At 3 months after treatment, the OHIP-14 score of group B was lower than that of group A (P<0.05). Conclusion The combined application of microscopic root canal therapy and periodontal tissue regeneration can improve the clinical efficacy of EPL, promote the improvement of periodontal indicators and the decrease of inflammatory indicators, so as to reduce the adverse effects of oral diseases on patients' health.