Objective To analyze the effect of periodontal guided tissue regeneration technique on periodontal indexes and clinical efficacy in patients with moderate to severe periodontitis. Methods A total of 50 patients with moderate to severe periodontitis who were treated in our hospital from January 2023 to October 2024 were selected as the research subjects, and they were divided into the control group and the study group by the random number table method, with 25 patients in each group. The control group was treated with conventional flap surgery, and the study group was treated with periodontal guided tissue regeneration technique. The clinical efficacy, periodontal indexes, aesthetic effect, quality of life and alveolar bone indexes were compared between the two groups. Results The total effective rate of treatment in the study group was 96.00%, which was higher than 72.00% in the control group (P <0.05). The plaque index, gingival index and sulcus bleeding index of the study group at 6 months after treatment were lower than those of the control group (P <0.05). The aesthetic effect score of the study group at 6 months after treatment was (11.53±1.02)scores, which was higher than (9.33±0.79)scores of the control group (P <0.05). The scores of oral function, psychological function, pain and discomfort and behavioral impact in the study group were lower than those in the control group (P <0.05). The alveolar bone height, width and bone mineral density of the study group at 6 months after treatment were higher than those of the control group (P <0.05). Conclusion The application of periodontal guided tissue regeneration technique in the treatment of moderate to severe periodontitis can effectively improve periodontal indexes, enhance clinical efficacy, and improve the aesthetics of anterior teeth area, thereby enhancing the quality of life.