Heart failure is a common public problem, the discovery of novel valid biomarkers is the key point of treatment, Chinese herbal medicine (TCM) encompasses a large number of herbal formulas with a wide variety of constituents, targets, and mechanisms that aid in treating disease. Compound Ginseng Astragalus (CGA) can be used to treat heart failure, but its mechanisms remain unclear. Proteomics science is an “-omic”, which has the common characteristics of systematic and integrated with TCM, advances in the field of quantitative proteomics such as data-independent acquisition (DIA) and parallel reaction monitoring (PRM) techniques have stimulated a large number of biomarker discovery studies of various diseases, providing avenues for new treatments and diagnostics. In this study, chronic heart failure (CHF) was induced by chronic sleep deprivation (CSD) combined with left anterior descending coronary artery ligation (LADCAL), and the CGA was given to intervene. Rats were divided into the control blank group (N), normal administration group (ND), model group (M), CGA group (D), and positive control group (Y). Cardiac function, ventricular remodeling, and histomorphology were measured after modeling, then, DIA and PRM-targeted proteomics were used to analyze serum samples from 4 control groups. The indexes of cardiac function showed that SV, EF, FS, and CO in group M were lower than those in group N (P < 0.05); The indexes of ventricular remodeling showed that LVIDs, LVEVs and LVEVd in group M increased (P < 0.05); LVAWs, lVAWd and lVPWs decreased (P < 0.05), and most indexes were corrected after CGA intervention. Myocardial inflammatory cell infiltration, tissue fibrosis, cell degeneration, and necrosis in group M were alleviated after CGA intervention. Proteomic results showed that a total of 88 differentially expressed proteins (DEPs) were found in 4 comparison groups. D / M was enriched in HSF1 activation pathway, ND / N was enriched in cell surface interactions at the vascular wall and immune interactions between a lymphoid and a non-lymphoid cell. The PRM detection results of Vwf and psma2 in the 4 groups were consistent with DIA. In conclusion, the phenotypic data showed the state of heart failure in the model group, the degree of heart failure was reduced after CGA intervention, some CHF biomarkers were revealed and verified from the perspective of proteomics, as well as the effect of CGA on the protein expression profile of CHF rats and normal rats, further provide ideas for the molecular mechanism of CHF and the pharmacological application of CGA.