Abstract: Objective To investigate the efficacy of sequential intravenous-to-oral butylphthalide therapy in vascular cognitive impairment (VCI) with hyperhomocysteinemia (HHcy). Methods A total of 154 patients with VCI and HHcy admitted to Xishan People's Hospital of Wuxi City were randomly divided into an intervention group (n=77) and a control group (n=77) in a 1∶1 ratio by a random number table. Both groups received conventional pharmacological treatment, while the intervention group was additionally treated with sequential intravenous-to-oral butylphthalide. Changes in mental status, cognitive function, activities of daily living (ADL), as well as homocysteine (Hcy) and inflammatory factor levels were compared between groups before and after treatment. Therapeutic efficacy and safety were also evaluated. Results After 3 and 6 months of treatment, both groups demonstrated significantly higher mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), and ADL scores compared to baseline (P＜0.05). The intervention group exhibited significantly higher MMSE, MoCA, and ADL scores than the control group at both time points (P＜0.05). After 6 months of treatment, levels of Hcy, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were significantly decreased in both groups compared to baseline (P＜0.05). Meanwhile, the levels of Hcy, IL-6, and TNF-α in the intervention group were lower than those in the control group (P＜0.05). After 6 months of treatment, the total effective rate in the intervention group was 94.81%, which was higher than that in the control group (80.52%, P＜0.05). No statistically significant difference was found in the occurrence of adverse reactions between the two groups (P＞0.05). Conclusion Sequential intravenous-to-oral butylphthalide therapy demonstrates robust efficacy and favorable safety in treating VCI with HHcy. It effectively improves mental status, cognitive function, ADL, and reduces Hcy and inflammatory factor levels.