The difference between hematocrit and serum albumin (HCT-ALB) demonstrates diagnostic significance in infectious diseases, yet the nonlinear relationship between HCT-ALB and hospital mortality in ICU patients with sepsis remains unexplored. This retrospective multicenter cohort study analyzed 7,546 ICU sepsis patients (mean age 66 ± 16 years) to elucidate the HCT-ALB-mortality relationship. Using Cox proportional hazards models with smooth curve fitting, we identified a U-shaped association: Threshold analysis revealed an inflection point at 6.1. Below this threshold, each unit HCT-ALB increase corresponded to reduced mortality risk (adjusted HR 0.986, 95%CI 0.972-0.999; P = 0.036). Conversely, values ≥ 6.1 predicted escalating risk (adjusted HR 1.048 per unit increase, 95%CI 1.037-1.060; P < 0.0001). Significant age interaction was observed (P for interaction < 0.05), with heightened mortality risk in elderly patients (≥ 65 years: HR 1.022, 95%CI 1.014-1.031). These findings establish HCT-ALB as a non-linear predictor of sepsis outcomes, emphasizing its critical threshold dynamics and age-dependent prognostic implications.