Background <p>Septic patients often face high mortality rates, influenced by various factors, including inflammation and nutritional status. This study investigates the relationship between the Advanced Lung Cancer Inflammation Index (ALI), an indicator of inflammation and nutritional status, and mortality rates (28-day, in-hospital, and ICU) in septic patients.</p> Methods <p>We conducted a retrospective analysis using data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, focusing on septic patients. Our primary analysis tools were multivariate logistic regression and restricted cubic spline (RCS) to examine the association between ALI and mortality outcomes. Additionally, subgroup and sensitivity analyses were performed to validate the findings.</p> Results <p>The study included 3,739 septic patients. Results showed that higher ALI levels were significantly associated with reduced 28-day and in-hospital mortality rates. Specifically, a one-unit increment in natural log-transformed ALI was linked to a 16% reduced risk of 28-day mortality (<i>p</i> &lt; 0.001) and a 12% reduced risk of in-hospital mortality (<i>p</i> = 0.002). These findings were consistent across different subgroups, confirming the stability of the results.</p> Conclusions <p>Elevated ALI levels are associated with lower mortality rates in septic patients, suggesting ALI as a potential prognostic marker for this group. However, further large prospective studies are needed to corroborate these findings and explore the implications for clinical practice.</p>