Objective To investigate the application effect of tinidazole, metronidazole combined with minocycline hydrochloride ointment in periodontitis. Methods A total of 100 patients with periodontitis admitted to Xi'an Beilin Rongkou Dental Clinic from May 2020 to February 2023 were randomly divided into study group and control group, with 50 patients in each group. The control group was treated with minocycline hydrochloride ointment, and the study group was treated with tinidazole and metronidazole on the basis of the control group. After 4 weeks of continuous treatment, the clinical efficacy, periodontal index improvement, inflammatory factor levels and adverse reactions were compared between the two groups. Results The total effective rate of treatment in the study group was 96.00%, which was higher than 78.00% in the control group (P<0.05). After treatment, PD, SBI, CAL and PLI in the study group were lower than those in the control group (P<0.05). After treatment, IL-1β, sICAM-1, CRP and MCP-1 in the study group were lower than those in the control group (P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P>0.05). Conclusion Tinidazole, metronidazole combined with minocycline hydrochloride ointment can effectively improve periodontal function, inhibit inflammatory reaction, have high clinical efficacy and safety, and have positive significance for promoting the rehabilitation of patients with periodontitis.