Background: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) particularly when coupled with acute respiratory failure (ARF), markedly elevates mortality rates. This investigation focuses on pivotal inflammatory markers in exacerbations of chronic obstructive pulmonary disease (COPD), including the neutrophil-to-lymphocyte ratio (NLR), lactate-to-albumin ratio (LAR), glucose-to-lymphocyte ratio (GLR), prognostic nutritional index (PNI), platelet-to-lymphocyte ratio (PLR), and systemic immune- inflammation index (SII), which are easily determinable from peripheral blood. We aimed to investigate the prognostic value of NLR, LAR, GLR, SII, PNI, and PLR for in-hospital mortality among AECOPD patients with ARF . Methods: This analysis encompassed data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, involving patients diagnosed with AECOPD and ARF. The study employed multivariate logistic regression and restricted cubic spline (RCS) models to evaluate the relationship between selected inflammatory markers and in-hospital mortality. The efficacy of these markers as prognostic tools was further assessed through receiver operating characteristic (ROC) curve analysis. Results: The study included 1,209 AECOPD patients with ARF, comprising 1,137 survivors and 72 fatalities, yielding an in-hospital mortality rate of 5.96%. Both NLR and PNI demonstrated non-linear relationships with mortality outcomes in RCS analysis, with inflection points at 6.66 and 43.54, respectively. Elevated GLR were linked with increased mortality risk. These results persisted even after adjusting for covariates. No significant associations were found for SII, LAR, or PLR. Notably, NLR [area under the curve (AUC) =0.684; 95% confidence interval (CI): 0.627-0.741] slightly surpassed PNI (AUC =0.663; 95% CI: 0.557-0.691) and GLR (AUC =0.624; 95% CI: 0.557-0.691) in predictive accuracy. Conclusions: NLR, GLR, and PNI on admission to hospital have moderate predictive utility for in- hospital mortality in patients with AECOPD and ARF. The findings may provide some references for exploring prognostic biomarkers and help clinicians to identify patients with AECOPD and ARF at elevated risk of mortality in an early stage.