Objective To investigate the effects of Qingre Huatan Tongluo Formula on microRNA-338-5p (miR-338-5p), inflammatory response, neurological function, and prognosis in patients with acute cerebral infarction.Methods A total of 125 patients with ischaemic stroke presenting with the phlegm-stasis obstructing collaterals syndrome, who were treated at the Department of Neurology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine between October 2022 and December 2024, were selected and divided into a control group (conventional treatment, 57 cases) and a traditional Chinese medicine (TCM) group (conventional treatment supplemented with the Qingre Huatan Tongluo Formula, 63 cases). Clinical data, laboratory indicator levels, National Institutes of Health Stroke Scale (NIHSS) scores, and modified Rankin Scale (mRS) scores were compared between the two groups, and the Spearman’s correlation analysis was performed.Results Laboratory parameters were compared between the TCM group and the control group at stroke onset, 72 h after onset, and day 10. The results demonstrated that significant differences were observed in the levels of miR-338-5p, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), neuron-specific enolase (NSE), total cholesterol, and low-density lipoprotein cholesterol among different time points (P < 0.05), whereas no significant differences were observed in white blood cell (WBC) count, neutrophil count (N), or levels of triglyceride, creatinine, and blood urea nitrogen (P > 0.05). Significant differences were observed between the TCM group and the control group in miR-338-5p, TNF-α, and NSE levels (P < 0.05). The TCM group had higher miR-338-5p levels and lower TNF-α and NSE levels than the control group. No significant differences were observed between the two groups in IL-6 levels, WBC count, neutrophil count, or levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol, creatinine, and blood urea nitrogen (P > 0.05). Significant differences were observed in the temporal trends of miR-338-5p, TNF-α, IL-6, NSE, and low-density lipoprotein cholesterol levels between the two groups (P < 0.05), whereas no significant differences were observed in the temporal trends of WBC count, neutrophil count, or levels of triglyceride, total cholesterol, creatinine, and blood urea nitrogen (P > 0.05). Serum miR-338-5p levels at 72 h after stroke onset were negatively correlated with 30-day mRS scores in both the control group and the TCM group (r_s = -0.438 and -0.468, respectively; both P < 0.05).Conclusion Qingre Huatan Tongluo Formula can improve inflammatory responses and short-term outcomes in patients with acute cerebral infarction. No drug-related adverse effects, including renal dysfunction, were observed during the observation period. Its neuroprotective effects may be associated with the upregulation of miR-338-5p.