〔Abstract〕 Objective To analyze the therapeutic effect of minocycline hydrochloride ointment combined with metronidazole oral adhesive tablets on patients with periodontitis. Methods A total of 178 patients with periodontitis admitted to Zhengzhou Stomatological Hospital from October 2021 to September 2023 were selected and divided into a control group and an observation group according to the principle of random grouping, with 89 cases in each group. The control group was treated with metronidazole oral adhesive tablets, and the observation group was treated with minocycline hydrochloride ointment on the treatment plan of the control group. Periodontal index, periodontal pocket depth (PD), gingival crevicular fluid inflammatory factors and clinical efficacy were compared between the two groups. Results The total clinical effective rate of the observation group was higher than that of the control group, and the difference was statistically significant (P < 0.05). After treatment, gingival index (GI), plaque index (PLI), sulcus bleeding index (SBI) and PD in the observation group were lower than those in the control group, and the differences were statistically significant (P < 0.05). After treatment, the levels of gingival crevicular fluid interleukin (IL) -6, IL-1β and matrix metalloproteinase (MMP) -8 in the observation group were lower than those in the control group, with statistical significance (P < 0.05). Conclusion Minocycline hydrochloride ointment combined with metronidazole oral adhesive tablet has achieved ideal effect in the treatment of periodontitis, which can significantly reduce gingival inflammation and improve periodontal pathologic status.