To provide evidence for the better clinical use of traditional Chinese medicine preparations (TCMPs), comparison of the pharmacological mechanisms between TCMPs with similar therapeutic effect is necessary. However, methodology for dealing with this issue is still scarce. Danhong injection (DHI) and Naoxintong capsule (NXT) are representative TCMPs for ischemic stroke (IS) treatment, which are also frequently used in combination. Here they were employed as research objects to demonstrate the feasibility of systems pharmacology approach in elucidation of the independent and combined effect of TCMPs. By incorporating chemical screening, target prediction, and network construction, a feasible systems pharmacology model has been established to systematically uncover the underlying action mechanisms of DHI, NXT, or their pair in IS treatment. Systematic analysis of the created TCMP-Compound-Target-Disease network revealed that DHI and NXT shared common targets such as PTGS2, F2, ADRB1, IL6, ALDH2, and CCL2, which were involved in the vasomotor system regulation, blood-brain barrier disruption, redox imbalance, neurotrophin activity, and brain inflammation. In comparative mechanism study, the merged DHI/NXT-IS PPI network and pathway enrichment analysis indicated that DHI and NXT exerted the therapeutic effects mainly through immune system and VEGF signaling pathways. Meanwhile, they had their own unique pathways, e.g., calcium signaling pathway for DHI and gap junction for NXT. While for their synergistic mechanism, DHI and NXT participated in chemokine signaling pathway, T cell receptor signaling pathway, VEGF signaling pathway, gap junction, and so on. Our study provided an optimized strategy for dissecting the different and combined effect of TCMPs with similar actions.