Objective To investigate the correlation between the levels of soluble suppression of tumorigenicity 2 (sST-2), high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and insulin-like growth factor-1 (IGF-1) with the severity of chronic heart failure (CHF).Methods A total of 73 patients with CHF admitted to Dezhou Hospital of Qilu Hospital, Shandong University, from January 2023 to June 2024, were selected as the heart failure group, while 80 healthy individuals undergoing physical examinations were selected as the control group. Serum levels of sST-2, hs-CRP, NT-proBNP and IGF-1 were compared between the two groups. The CHF group was further divided into three subgroups based on left ventricular ejection fraction (LVEF): heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). The serum levels of IGF-1, sST-2, and hs-CRP among the three subgroups were compared. The correlation between serum levels of sST-2, hs-CRP, NT-proBNP, and CHF severity, as well as their diagnostic value for CHF severity, was analyzed. Multivariate stepwise Logistic regression was used to analyze the influencing factors of heart failure. Spearman correlation analysis was performed to assess the relationship between serum sST-2, hs-CRP, and NT-proBNP levels and the severity of heart failure. Receiver operating characteristic (ROC) curves were plotted to evaluate the diagnostic value of serum sST-2, hs-CRP, NT-proBNP levels, and their combined assessment for the severity of heart failure.Results Serum levels of sST-2, hs-CRP, and NT-proBNP in the CHF group were significantly higher than those in the control group (P < 0.05), while IGF-1 levels were lower (P < 0.05). The HFrEF subgroup exhibited significantly higher serum levels of sST-2, hs-CRP, and NT-proBNP compared to the HFmrEF and HFpEF subgroups (P < 0.05), and the HFmrEF subgroup showed higher levels than the HFpEF subgroup (P < 0.05). Spearman correlation analysis indicated that sST-2, hs-CRP, and NT-proBNP levels were negatively correlated with LVEF and positively correlated with left ventricular end-diastolic diameter (LVEDD) and LVEF grading (P < 0.05). The results of the multivariate stepwise logistic regression analysis showed that LVEF [O^R = 0.679 (95% CI: 0.514, 0.897) ] was a protective factor (P < 0.05), while LVEDD [O^R = 1.224 (95% CI: 1.053, 1.422) ], sST-2 [O^R = 1.175 (95% CI: 1.007, 1.372) ], hs-CRP [O^R = 1.428 (95% CI: 1.021, 1.998) ], and NT-proBNP [O^R = 1.001 (95% CI: 1.000, 1.002) ] were all risk factors for the severity of heart failure (P < 0.05). The results of the ROC curve analysis showed that the areas under the curve for sST-2, hs-CRP, and NT-proBNP were 0.774, 0.770, and 0.689, respectively. The area under the curve for the combined detection of the three indicators was 0.883, which had a higher diagnostic value than any single indicator.Conclusion Serum levels of sST-2, hs-CRP, and NT-proBNP are positively correlated with the severity of CHF, increasing with the progression of the disease. The combined diagnostic value of sST-2, hs-CRP, and NT-proBNP is higher than that of any single biomarker, providing high diagnostic specificity and offering a novel approach for assessing CHF severity.