Aims. To investigate the effect of Vitapex combined with AH-plus paste on inflammation in middle-aged and elderly patients with periodontal-endodontic disease. Materials and Methods. A total of 80 teeth of middle-aged and elderly patients with the periodontal-endodontic disease who were treated in our hospital from June 2020 to June 2021 were selected as the research objects and were divided into comparison group and treatment group with 40 teeth each according to different treatment methods. Among them, the comparison group was filled with zinc oxide clove oil paste gutta-percha, and the treatment group was filled with Vitapex combined with AH-plus paste. The changes in apical cross-section sealing performance, periodontal pocket depth (PD), and gingival index (GI) of the two groups before treatment and after 6 months of follow-up were observed and compared, and X-ray analysis was performed. Results. There was no significant difference in the level of periodontal indexes and serum inflammatory indexes between the two groups before treatment (
P
>
0.05
). After treatment, the levels of PD, BI, PLI, and GI in the two groups were significantly lower than before treatment (
P
<
0.05
). The differences in IL-6, IL-10, TNF-α, and IL-1β after treatment were significant (
P
<
0.05
). There was no significant difference in the root canal area data of each cross-section between the two groups when the root canal was filled with root filling paste at different positions from the apex (
P
>
0.05
). After root canal filling with root canal paste, the cross-sectional area from different parts of the root canal in the treatment group was significantly smaller than comparison group (
P
<
0.05
). After 6 months of treatment, it was found that CEJ-BD and CEJ-AC in the treatment group were significantly lower than those in the comparison group (
P
<
0.05
). Conclusion. Vitapex combined with AH-plus paste filling can effectively treat middle-aged and elderly periodontal-endodontic disease, which provides a certain reference for the clinical treatment of middle-aged and elderly periodontal-endodontic disease.