Objective To explore and analyze the expression and prognostic value of serum vitamin D (VitD), ferritin (FRT) and heparin-binding epidermal growth factor (HB-EGF) in sepsis patients. Methods 86 sepsis patients who were admitted to the intensive care unit (ICU) of a hospital from January 2021 to January 2022 were selected as the case group, and 60 non-sepsis patients in the ICU were selected as the control group. According to the prognosis of sepsis patients one month later, patients were divided into survival group and death group. Patient's serum upon admission was taken, levels of serum VitD, FRT and HB-EGF were detected, the correlation with the prognosis of sepsis patients was analyzed, and the prognostic value was evaluated by area under curve (AUC) of receiver opera-ting characteristic curve. Results Levels of white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor-α(TNF-α), interleukin (IL)-6, IL-1β and FRT of case group were all higher than those of non-sepsis patients in the control group, while the VitD and HB-EGF levels were lower than those of non-sepsis patients in the control group, differences were all statistically significant (all P < 0.05). One month follow-up on the prognosis of sepsis patients showed that 55 patients survived and 31 died. Acute physiology and chronic health evaluationⅡ (APACHE Ⅱ) score, sequential organ failure assessment (SOFA) score, PCT, TNF-α, IL-1β and FRT score in patients in the death group were all higher than those in patients in the survival group, while VitD and HB-EGF were lower than patients in the survival group, differences were all statistically significant (all P < 0.05). The Pearson correlation analysis results showed that VitD were negatively correlated with APACHE Ⅱ score, SOFA score, WBC, CRP, PCT and TNF-α(all P < 0.05), HB-EGF was negatively correlected with APACHE Ⅱ, score, CRP, PCT, TNF-α, IL-6 and IL-1β (all P < 0.05); while FRT was positively correlated with APACHE Ⅱ scores, CRP, PCT, TNF-α, IL-6 and IL-1β (all P < 0.05). The AUC, sensitivity, and specificity of combined detection of serum VitD, FRT and HB-EGF in predicting the prognosis of sepsis patients were 0.82 (95%CI: 0.72-0.86), 84.39%, and 69.35%, respectively. Conclusion Serum levels of VitD and HB-EGF are lower and FRT is higher in sepsis patients, their expression levels are closely related to patient prognosis, and have good predictive value for predicting the prognosis of sepsis patients.