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Objectives This study aims to explore the correlation between the prognostic nutritional index (PNI) and all-cause mortality in patients diagnosed with ischemic stroke (IS). Methods A single-center retrospective cohort study was conducted at Dandong Central Hospital, enrolling 1,152 consecutive patients with IS who were discharged from January to December 2024. Multivariate Cox regression models, subgroup analysis, sensitivity analysis, receiver operating characteristic (ROC) curve, and Kaplan–Meier survival analysis were employed to investigate the association between the PNI and all-cause mortality. Results During a median follow-up period of 14.23 months, a total of 96 (8.3%) patients experienced all-cause mortality. Multivariate Cox regression analysis showed that after adjusting for multiple confounding factors, each 1-unit increase in PNI was associated with an 8.5% reduction in all-cause mortality risk (hazard ratio [HR] = 0.915, 95% confidence interval [CI]: 0.883–0.947, p < 0.001), each 1-standard deviation increase was associated with a 40.1% reduction in all-cause mortality risk (HR = 0.599, p < 0.001). Compared with the lowest PNI quartile (Q1, PNI ≤ 44.16), the Q2 (PNI: 44.16–44.75) had a 54.1% lower risk of all-cause mortality (HR = 0.459, p = 0.004), the Q3 (PNI: 44.75–51.30) had a 56.4% lower risk of all-cause mortality (HR = 0.436, p = 0.007), the Q4 (PNI > 51.30) had a 72.6% lower risk of all-cause mortality (HR = 0.274, p < 0.001). Multiple subgroup and sensitivity analyses further confirmed the robustness of these associations. Stratified analyses based on various cutoff values of PNI uniformly demonstrated that patients with higher PNI levels had a notably reduced risk of all-cause mortality compared to those with lower PNI levels. ROC curve analysis indicated that PNI had favorable predictive value for all-cause mortality (overall population, AUC = 0.710; male, AUC = 0.720; female, AUC = 0.703; all p < 0.001). Kaplan–Meier survival curve analysis revealed significant differences in cumulative all-cause mortality risk among different PNI groups, with higher PNI levels correlating with lower cumulative mortality risk (Log-rank p < 0.001). Conclusion The PNI establishes itself as an independent prognostic biomarker in IS patients, with higher levels correlating with a lower all-cause mortality risk.