Abstract: The Shenqi Fuzheng (SQ) formula, made from Codonopsis Radix (Dangshen, DS) and Astragali Radix (Huangqi, HQ), has been used in Traditional Chinese Medicine (TCM) and exhibits cardio-protective effects against acute myocardial infarction (AMI). However, the molecular basis of DS-HQ synergy remains unclear. Here, we combined RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) to explore their synergistic mechanisms. Transcriptomic analyses showed that SQ influenced the AMI network more effectively than either herb alone. ScRNA-seq analysis revealed that these synergistic effects involve both direct and indirect pro-angiogenic pathways. The combination treatment synergistically activates microvascular endothelial subpopulations and promotes angiogenesis in the border zone. It also enhances the anti-inflammatory role of a specific reparative macrophage subset and stimulates increased vascular endothelial growth factor A (VEGFA) secretion from these cells, supporting the VEGFA-VEGFR interaction between macrophages and microvascular endothelial cells. This coordinated regulation provides a plausible mechanistic explanation for the reduced infarct size and improved cardiac outcomes seen in vivo, highlighting the therapeutic value of TCM.