Objective <p>To investigate the effect and safety of Yihuo Huatan Formula (YHF) on stable chronic obstructive pulmonary disease (COPD) patients with Chinese medicine (CM) syndrome of qi deficiency, blood stasis, and phlegm turbidity (QDBSPT) and explore its therapeutic mechanism.</p> Methods <p>This is a randomized, double-blind and placebo-controlled trial. Totally 96 stable COPD patients with QDBSPT syndrome were recruited from the outpatient clinic of the Department of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University from February 2022 to December 2022 and randomized into 2 groups to receive YHF (1 packet/time, thrice a day, YHF group) or placebo (control group) for 2 consecutive months, 48 cases per group. All patients in both groups received their standard treatment and conventional medications. The primary outcome was number of moderate or severe acute exacerbations of COPD during 12-month follow-up. The secondary outcomes included number of emergencies or hospital admissions and length of hospital stay due to COPD exacerbations during 12-month follow-up, changes from baseline in COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ), and St. George’s Respiratory Questionnaire (SGRQ) scores, total effective rates of CM syndrome, pulmonary function, and plasma inflammatory cytokine levels, etc. The potential adverse effects were monitored during the study. After treatment, metabolomic and 16S rRNA gene sequencing analyses were performed on fecal samples from participants in both groups to investigate the therapeutic mechanism of YHF.</p> Results <p>Forty-one patients in the YHF group and 43 in the control group completed the trial. YHF treatment significantly reduced the risk of acute COPD exacerbations, including the numbers of moderate or severe acute exacerbations [relative risk (RR) 0.468; 95% CI 0.31–0.71; <i>P</i>&lt;0.001] and emergency or hospital admissions (RR 0.500; 95% CI 0.27–0.93; <i>P</i>=0.028), during the 12-month follow-up period. After 2 months of treatment and at the 2- and 4-month follow-ups, there was a statistically significant improvement in the total effective rate of YHF for the CM syndrome (<i>P</i>&lt;0.05). In addition, changes in the scores of the CAT, CCQ, and SGRQ from baseline were significantly greater in the YHF group than in the control group after treatment and at the 12-month follow-up (<i>P</i>&lt;0.05). There were no significant differences in the levels of inflammatory cytokines and lung function (<i>P</i>&lt;0.05). No adverse effects were reported in response to the intervention. The efficacy of YHF was associated with increased gut microbiota diversity and altered <i>Firmicutes</i> abundance, notably elevating the abundance of <i>Faecalibacterium prausnitzii</i>.</p> Conclusions <p>YHF is a promising therapeutic option for stable COPD patients with QDBSPT syndrome. Its mechanism involves fecal metabolic regulation and modulation of gut microbiota, particularly through elevating <i>Faecalibacterium prausnitzii</i> level. (Trial registration No. ChiCTR2100051149)</p>