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Background Localized aggressive periodontitis is rare periodontitis in clinical practice, which often occurs in young adults under 35 years old, seriously affecting patients' quality of life. As a tetracycline antibacterial drug, minocycline is also considered an essential choice to treat periodontal disease. However, few reports focused on the effect of xipayi mouth rinse combined with minocycline on periodontal pathogens. The goal of this study was to investigate the clinical effect of xipayi mouth rinse combined with minocycline in the treatment of localized aggressive periodontitis and its effect on the levels of CRP, TNF-α, and IL-6. Methods Ninety-six patients with limited aggressive periodontitis were selected and randomly divided into two groups. Forty-eight patients in the control group were treated with xipayi mouth rinse after primary periodontal treatment. Then, 48 patients in the experimental group were treated with xipayi mouth rinse combined with minocycline after primary periodontal treatment. The periodontal probe was applied to detect periodontal plaque index (PLI), periodontal pocket depth (PD), sulcus bleeding index (SBI), gingival index (GL), and clinical attachment loss (CAL) before and after treatment in both groups of patients. ELISA was used for detecting the expression levels of CRP, TNF-α, and IL-6 in the serum of patients in two groups before and after treatment. We compared the recurrence rates of the two groups after a 1-year follow-up. Results Compared with the control group, the PLI, PD, SBI, GL, CAL, and total masticatory efficiency of the experimental group were significantly better than those of the control group. The levels of inflammatory factors CRP, TNF-α, and IL-6 were significantly declined, and the total effective rate of treatment was significantly elevated. After follow-up, it was found there was no noticeable difference in the recurrence rate between the two groups. Conclusions Xipayi mouth rinse, combined with minocycline in the treatment of localized aggressive periodontitis, can significantly improve the periodontal gingival condition and reduce the level of inflammatory factors. Also, the efficacy of the treatment was significant. This experiment has provided ideas for improving the clinical treatment of patients with localized aggressive periodontitis.