Abstract: Objective To evaluate the efficacy and safety of modified Zhenfang Baiwan Formula combined with butylphthalide and sodium chloride injection in the treatment of acute ischemic stroke (AIS) with wind-phlegm invading collaterals type. Methods This prospective study enrolled 96 AIS patients characterized by the wind-phlegm invading collaterals syndrome who were admitted to Fuyang Traditional Chinese Medicine Hospital from January 2022 to April 2025. Patients were randomly divided into the control group and the observation group (n = 48 in each group) using a random number table. The control group received conventional treatment with butylphthalide and sodium chloride injection, while the observation group was additionally treated with modified Zhenfang Baiwan Formula on the basis of the control treatment. The clinical effective rates, Traditional Chinese Medicine (TCM) syndrome scores and neurological function were compared before and after treatment between the two groups, and adverse reactions during treatment were recorded to evaluate safety. Results The observation group demonstrated a significantly higher clinical efficacy rate compared to the control group (P < 0.05). Regarding TCM syndromes, the observation group exhibited significantly lower scores for speech impairment, facial deviation, and hemiplegia than the control group after treatment (P < 0.05). For neurological recovery, both groups showed significant improvements, as indicated by reduced National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores post-treatment compared to baseline (P < 0.05). The observation group achieved a significantly greater degree of recovery, evidenced by higher △NIHSS and △mRS scores relative to the control group (P < 0.05). There was no statistical difference in the incidence of adverse reactions between the observation group and the control group (P = 0.642). Conclusion The modified Zhenfang Baiwan Formula combined with butylphthalide and sodium chloride injection yields satisfactory clinical efficacy in the treatment of AIS with the syndrome of wind-phlegm invading collaterals. It can ameliorate neurological function and TCM syndromes with favorable safety.