Objective To investigate the clinical effect of multi-antibiotic paste in the treatment of pulp disease with periapical disease. Methods A total of 70 patients with pulposis and periapical periodontitis admitted to the Department of Stomatology, the Seventh Affiliated Hospital of Xinjiang Medical University and the First Affiliated Hospital of Shihezi University from September 2021 to July 2022 were selected as the research objects. All patients were treated with root canal filling and were divided into control group and study group according to different fillers, with 35 cases in each group. The control group was filled with Vitapex paste, and the study group was filled with multi-antibiotic paste. The clinical efficacy, pain degree, inflammatory factor level, adverse reactions and satisfaction were compared between the two groups. Results The total effective rate of treatment in the study group was 94.29%, which was higher than 88.57% in the control group, and the difference was not statistically significant ( P >0.05). The VAS score of the two groups after treatment were lower than that before treatment, and that in the study group was lower than that in the control group ( P <0.05). After treatment, the levels of IL-6, CRP and TNF-α in the two groups were lower than those before treatment, and those in the study group were lower than those in the control group ( P <0.05). The total incidence of adverse reactions in the study group was lower than that in the control group, and the difference was not statistically significant ( P >0.05). The satisfaction of the study group was 97.14%, which was higher than 80.00% of the control group ( P <0.05). Conclusion The efficacy and safety of multi-antibiotic paste and Vitapex paste are comparable in the treatment of pulp disease with periapical disease, but multi-antibiotic paste is more conducive to inhibiting inflammation, improving analgesic effect and treatment satisfaction than Vitapex paste.