To explore the application value of periodontal therapy at different times after root canal therapy in patients with combined periodontal-endodontic lesions. Methods A total of 90 patients with combined periodontal-endodontic lesions admitted to our hospital from January to December 2022 were selected and divided into observation group and control group according to the random number table method, with 45 patients in each group. The control group was given periodontal treatment at 3 weeks after root canal treatment, and the observation group was given periodontal treatment at 1 week after root canal treatment. The clinical efficacy, periodontal pocket probing depth (PD), plaque index (PLI), interleukin-8 (IL-8), interleukin-6 (IL-6), pain rate [visual analogue scale (VAS) score] and complication rate were compared between the two groups. Results The total effective rate of treatment in the observation group was 97.78%, which was higher than 80.00% in the control group (P <0.05). PD and PLI in the observation group were lower than those in the control group (P <0.05). The levels of IL-8 and IL-6 in the observation group were lower than those in the control group (P <0.05). The pain rate of the observation group was 8.89%, which was lower than 37.78% of the control group (P <0.05). The incidence of complications in the observation group was 4.44%, which was lower than 20.00% in the control group (P <0.05). Conclusion Periodontal treatment at 1 week after root canal therapy can improve the therapeutic effect, periodontal index, gingival crevicular fluid inflammatory factors, and reduce the pain and the incidence of complications in patients with combined periodontal-endodontic lesions, which is worthy of clinical application.