This study aims to investigate the effectiveness of combining serum lectin galactoside-binding soluble 3 binding protein (LGALS3BP) with growth differentiation factor 15 (GDF-15) for predicting outcomes in sepsis patients in an intensive care unit (ICU) setting. The study involved 208 sepsis patients from the ICU of our hospital. These patients were categorized based on their 28-day survival outcomes into two groups: 166 in the survival group and 42 in the mortality group. The serum levels of LGALS3BP and GDF-15 were measured using the ELISA technique. Pearson and Spearman methods were utilized for correlation analysis. Factors affecting mortality in ICU sepsis patients were evaluated through multivariate logistic regression analysis. The efficacy of these biomarkers in prognosis prediction was assessed using receiver operating characteristic (ROC) curve analysis. The proportion of septic shock, APACHE II score, SOFA score, and serum LGALS3BP and GDF-15 levels in ICU sepsis patients in the death group were obviously higher than those in the survival group (P<0.05). The severity of ICU sepsis patients, APACHE II score, and SOFA score were obviously positively correlated with serum LGALS3BP and GDF-15 levels (P<0.05). LGALS3BP (OR: 95% CI=2.745:1.583~4.761) and GDF-15 (OR: 95% CI=2.639:1.423~4.893) were independent risk factors for death in ICU sepsis patients (P<0.05). The AUC of serum LGALS3BP and GDF-15 levels alone in predicting death in ICU sepsis patients was 0.859 and 0.854, obviously lower than the AUC of the combination, 0.943 (Z=2.704, 2.287, P<0.05). The AUC for predicting mortality in ICU sepsis patients using the APACHE II and SOFA scores were 0.832 and 0.842, respectively. The differences in comparison to the AUCs of LGALS3BP and GDF-15 were not statistically significant (P > 0.05). Serum levels of LGALS3BP and GDF-15 can both be used as predictive indicators for death in ICU sepsis patients, and their combined predictive efficacy is better.