Objective To evaluate the clinical efficacy of a triple therapeutic regimen consisting of minocycline, tinidazole, and compound chlorhexidine in patients with chronic periodontitis (CP), and to analyze its impact on inflammatory cytokines and the periodontal microbiota. Methods Seventy patients with CP who were treated in the Department of Stomatology, Hengdian Hospital of Dongyang City from June 2022 to June 2025 were selected as the research objects. The selected patients were randomly divided into control group (standard treatment＋tinidazole＋compound chlorhexidine) and observation group (minocycline ointment was added on the basis of the control group), with 35 patients in each group. Imaging and clinical examination were used to evaluate the changes of periodontal indexes, inflammatory factors [interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)] and periodontal microecology in the two groups before and after treatment for 3 months. Results The total effective rate in the observation group (97.14%) was significantly higher than that in the control group (77.14%) (P＜0.05). After treatment, the periodontal clinical indexes and inflammatory factors in the two groups were significantly better than those before treatment (all P＜ 0.05), and the improvement of the above indexes in the observation group was even greater (all P＜0.05). In terms of microecology, the decrease of pathogen abundance and the recovery of diversity in the observation group were significantly better than those in the control group (all P＜0.05). The adverse reactions of the two groups were mild, without special treatment, and relieved by themselves after stopping the drug. There was no significant difference in the total incidence of adverse reactions between the two groups (P＞ 0.05). Conclusion Minocycline triple regimen is effective in the treatment of CP, which can significantly improve periodontal condition, inhibit inflammatory reaction and reshape periodontal microecological balance, with high safety.