Background: Patients aged 80 years and above are at increased risk for severe COVID-19 outcomes. This study aimed to evaluate the prognostic utility of the derived neutrophil-to-lymphocyte ratio (dNLR), aspartate-aminotransferase-to-lymphocyte ratio index (ALRI), aspartate-aminotransferase-to-platelet ratio index (APRI), and systemic immune inflammation index (SII) in predicting severe disease, intensive care unit (ICU) admission, and mortality among COVID-19 patients aged 80 years and older. Methods: In this retrospective cohort study, 138 elderly patients (≥80 years) and 215 younger controls (<65 years) with confirmed COVID-19 were included. Laboratory data at admission were collected, and the dNLR, ALRI, APRI, and SII scores were calculated. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive performance of these indices. Results: The SII had the highest area under the ROC curve (AUC) for predicting severe disease in elderly patients (AUC = 0.857, 95% CI: 0.795–0.919, p < 0.001), with an optimal cutoff value of 920 × 10⁹/L (sensitivity 86%, specificity 78%). Elevated SII was significantly associated with increased risk of ICU admission (hazard ratio (HR): 2.9, 95% CI: 1.8–4.6, p < 0.001) and mortality (HR: 3.2, 95% CI: 1.9–5.2, p < 0.001). Similarly, dNLR showed good predictive value (AUC = 0.792, 95% CI: 0.722–0.862, p < 0.001). Conclusions: SII and dNLR are valuable prognostic biomarkers for predicting severe outcomes in COVID-19 patients aged 80 years and above. Early identification using these indices can assist clinicians in risk stratification and management decisions to improve patient outcomes.