Objective To explore the evaluation value of serum soluble triggering receptor expressed on myeloid cells-like transcript 1 (sTLT-1), surfactant protein-D (SP-D) and nuclear transcription factor-κB (NF-κB) for prognosis of sepsis combined with acute lung injury (ALI). Methods A total of 36 patients with sepsis and 80 patients with sepsis and ALI in the hospital were enrolled as sepsis group and ALI group from April 2021 to April 2023, respectively. The general data, levels of serum sTLT-1, SP-D and NF-κB, scores of APACHE Ⅱ and LIPS in the two groups were compared. According to 1-month survival, patients in ALI group were divided into death group (n=32) and survival group (n=48), and general data, levels of serum sTLT-1, SP-D and NF-κB, scores of APACHE Ⅱ and LIPS in the two groups were compared. The influencing factors of poor prognosis in ALI group and the evaluation value of the three serological indexes for prognosis of ALI were analyzed. Results The levels of sTLT-1, SP-D and NF-κB, scores of APACHE Ⅱ and LIPS in ALI group were higher than those in sepsis group (P＜0.05). Univariate analysis showed that there was no significant difference in gender, age, infection sites, number of smoking cases or BMI level between death group and survival group (P＞0.05). The levels of sTLT-1, SP-D and NF-κB, scores of APACHE Ⅱ and LIPS in death group were higher than those in survival group (P＜0.05). Multivariate analysis showed that serum sTLT-1, SP-D, NF-κB, APACHE Ⅱ score and LIPS score were independent risk factors of poor prognosis in ALI patients. ROC curves analysis showed that AUC of sTLT-1 combined with SP-D and NF-κB in the diagnosis of poor prognosis was 0.914, greater than that of single index (0.832, 0.796, 0.816). Conclusion The levels of serum sTLT-1, SP-D and NF-κB are related to the occurrence and development of sepsis combined with ALI, and they are also independent risk factors of poor prognosis. Clinically, combined detection of the three indexes is beneficial to guide the prognosis evaluation of ALI