To explore the effects of modified Huanglian Wendan Decoction based on syndrome differentiation on brain-derived neurotrophic factor (BDNF), neurotransmitters, and National Institutes of Health Stroke Scale (NIHSS) scores in patients with post-stroke depression (PSD). Methods: A total of 106 PSD patients admitted to our hospital from January 2023 to April 2024 were selected and randomly divided into a control group and a TCM group using a random number table, with 53 patients in each group. The control group received conventional treatment, while the TCM group was additionally given modified Huanglian Wendan Decoction on the basis of conventional treatment. The Hamilton Anxiety Scale (HAMA) score, Hamilton Depression Scale (HAMD) score, Activity of Daily Living (ADL) score, NIHSS score, levels of BDNF, glial cell line-derived neurotrophic factor (GDNF), neurotransmitters, and cognitive function were compared between the two groups before and after treatment. Results: Before treatment, there were no statistically significant differences in HAMA, HAMD, ADL, NIHSS, Montreal Cognitive Assessment (MoCA) scores, or levels of BDNF, GDNF, 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE) between the two groups (P > 0.05). After treatment, the HAMA, HAMD, and NIHSS scores of the TCM group were lower than those of the control group, while the ADL score, MoCA score, and levels of BDNF, GDNF, 5-HT, DA, and NE were higher than those of the control group (P < 0.05). Conclusion: Modified Huanglian Wendan Decoction based on syndrome differentiation in the treatment of PSD is beneficial for increasing the levels of neurotransmitters and neurotrophic factors in patients, reducing depression and anxiety, and improving patients’ cognitive function and quality of life.