Objective To identify the blood-entering components of HanJing Decoction (HJT) after administration based on UPLC-QE-MS/MS, and the key components, therapeutic targets and mechanisms of HJT therapeutic coronary heart disease (CHD) were analyzed using network pharmacology and molecular docking. Method The UPLC-QE-MS/MS was used to analyze the blood-entering components of HJT before and after administration. The targets of blood-entering components were predicted by SwissTargetPrediction. Targets related to CHD were collected using multiple databases. The GO and KEGG enrichment analyses were used to predict the mechanisms of HJT therapeutic CHD, and PPI and “Components-Targets-Pathways” network were used to identify and elucidate the core targets. The key blood-entering components aimed at the core target are screened by molecular docking and QSAR analysis. Results A total of 14 blood-entering components were detected in serum samples of rat after administration, and the 32 potential targets of HJT therapeutic CHD were screened out. The result of PPI network showed that the core targets of HJT for the treatment of CHD include MMP1, GSK3B, EGFR and PTGS2, and the 5 key components with high degree were screened out. The GO and KEGG enrichment analyses indicate that HJT therapy for CHD is associated with the IL-17 and cGMP-PKG signaling pathways. The result of molecular docking indicate that the binding energy of coroglaucigenin to PTGS2 is the largest and it may be the key pharmacological component of HJT, and the QSAR analysis showed that Boldine and Coroglaucigenin had excellent activity in inhibiting PTGS2. Conclusions In this study, the blood-entering components of HJT were preliminarily identified, Combined network pharmacology and molecular docking analyses revealed that the PTGS2 may be a core target, and the IL-17 and cGMP-PKG signaling pathways may be the key pathways. Moreover, the coroglaucigenin and boldine may be the key pharmacological components of HJT.