Background <p>Inflammation plays a critical role in the pathogenesis of both sepsis and cirrhosis. The neutrophil-to-lymphocyte ratio (NLR), a composite inflammatory marker, has garnered increasing attention. However, the association between NLR and the risk of mortality in patients with cirrhosis and sepsis remains unclarified.</p> Methods <p>Clinical information on patients with cirrhosis and sepsis was sourced from the MIMIC-IV (Medical Information Mart for Intensive Care IV) database. Clinical endpoints were all-cause mortality. The link between NLR and mortality was examined through restricted cubic splines (RCS), logistic regression, and Cox regression analyses. The predictive value of NLR for in-hospital all-cause mortality in individuals with liver cirrhosis and sepsis was investigated using Receiver Operating Characteristic (ROC) analysis. Subgroup analysis was implemented to check the consistency of the association.</p> Results <p>A total of 1,372 patients were enrolled and stratified into a survival group (<i>n</i> = 1,271) and a non-survival group (<i>n</i> = 101) based on in-hospital survival status, yielding a mortality rate of 7.4%. In the unadjusted model, a notable link was revealed between NLR and all causes of death in septic patients with cirrhosis (Odds ratio [ORs]: 1.03, 95% Confidence intervals [CI]: 1.02–1.04, <i>P</i> &lt; 0.001). RCS analysis revealed a nonlinear association between NLR and mortality risk (<i>P</i> for nonlinearity &lt; 0.001; <i>P</i> for overall association &lt; 0.001). ROC curves uncovered a higher Area Under the Curve (AUC) for NLR (0.752) than that for sequential organ failure assessment (SOFA) scores (0.711). Subgroup analysis indicated no pronounced interaction between NLR and etiology (interaction <i>P</i> &gt; 0.05).</p> Conclusion <p>NLR is an independent risk factor for in-hospital all-cause death in septic patients with cirrhosis, and it can guide interventions for this high-risk population.</p>