〔Abstract〕 Objective To analyze the efficacy and safety of Xiaoqinglong decoction in the treatment of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with exterior cold and interior fluid retention syndrome. Methods Ninety-two AECOPD patients admitted to Chancheng District People’s Hospital of Foshan City from May 2020 to June 2022 were selected as the research subjects. According to the random number table method, they were divided into a control group and an observation group, with 46 cases in each group. The control group received conventional Western medicine treatment, while the observation group received Xiaoqinglong decoction treatment on the basis of the control group. The Traditional Chinese Medicine (TCM) syndrome scores (cough, expectoration, wheezing, chest tightness, shortness of breath, and phlegm noise in the throat), the peripheral blood levels of cluster of differentiation (CD) 4⁺ , CD8⁺ , CD4⁺ /CD8⁺ , tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and nitric oxide (NO), as well as blood, urine, stool, and liver and kidney function test indicators, and adverse events during treatment were compared between the two groups before and after treatment. Results After treatment, the TCM syndrome scores of both groups were lower than those before treatment, and the TCM syndrome scores of the observation group were lower than those of the control group, with statistically significant differences (P < 0.05). After treatment, the serum levels of PCT, TNF-α, and NO of both groups were lower than those before treatment, and the serum levels of PCT, TNF-α, and NO of the observation group were lower than those of the control group, with statistically significant differences (P < 0.05). After treatment, the CD4⁺ and the ratio of CD4⁺ /CD8⁺ of both groups were higher than those before treatment, and CD8⁺ was lower than that before treatment. The peripheral blood levels of CD4⁺ and the ratio of CD4⁺ /CD8⁺ of the observation group were higher than those of the control group, and CD8⁺ was lower than that of the control group, with statistically significant differences (P < 0.05). After treatment, there were no significant abnormalities in liver and kidney function indicators, blood, urine, and stool routine in both groups, and no adverse events occurred in either group during the treatment. Conclusion Conventional Western medicine treatment combined with Xiaoqinglong decoction can better relieve the TCM syndromes of AECOPD patients with exterior cold and interior fluid retention syndrome, improve immune function, inflammation, and oxidative stress indicators, with high safety.