The present study aimed to explore the neuroprotective mechanism of Di Dang decoction (DDD) during acute intracerebral hemorrhage (AICH) stroke in Sprague Dawley rats through proteomic analysis.A total of 135 healthy Sprague Dawley rats were randomly divided into five groups: control (n = 27), model (n = 27), DDD low-dose (n = 27), DDD medium-dose (n = 27), and DDD high-dose (n = 27). AICH stroke in rats was induced by injecting autologous blood into the caudate nucleus. The modified Neurological Severity Score (mNSS) was used to evaluate the cerebral nerve function deficit. Hematoxylin and eosin (HE) staining was performed to observe the brain tissue at the lesion site. Albumin concentration was assessed on obvious blood-brain barrier damaged and brain water content was used to evaluate the brain injury. For quantitative proteomics, proteins were extracted from the cerebral cortices. Target proteins were identified using mass spectrometer-based targeted proteomic quantification.mNSS score, HE staining results, albumin concentration, and brain water content showed the most significant improvements in the neuroprotective in the high-dose group 7 days after DDD exposure. Furthermore, quantitative proteomics analysis showed that, relative to the control group, S100a8 and S100a9 were downregulated by 0.614 (p = 0.033702) and 0.506 times (p = 0.000024) in the high-dose group. Compared with the control group, Col1a1 and Col1a2 were upregulated by 1.319 (p = 0.000184) and 1.348 (p = 0.014097) times in the high-dose group. These results were confirmed using mass spectrometer-based targeted proteomic quantification.Application of a high-dose DDD for 7 days in AICH stroke rats showed the most significant improvements in neuroprotective. Mechanistically, this effect was mediated by S100a8 and S100a9 protein downregulation and Col1a1 and Col1a2 upregulation.