Background: The present study aimed at determining and comparing the prognostic value and the relationship of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios (PLRs) with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Materials and Methods: The present case–control study was performed on 100 chronic obstructive pulmonary disease patients and 100 healthy subjects (controls). Age, gender, and laboratory results of complete blood count tests including lymphocyte count, neutrophil count, platelet count, hemoglobin level, neutrophil-to-lymphocyte ratio (NLR), PLR, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were obtained from the patient report and then recorded. The mentioned information was also completed for the control group. Following hospitalization, the patients that were discharged with clinically stable general status were re-examined, and the aforementioned laboratory information was rerecorded. Results: The results of the present study revealed that NLR with the sensitivity and specificity of 83.00% (74.2%–89.8%) and 93.00% (86.1%–97.1%) (cutoff value of 2.3), PLR with the sensitivity and specificity of 56.00% (46.0%–66.3%) and 83.00% (74.2%–89.8%) (cutoff value of 135.8), white blood cell (WBC) with the sensitivity and specificity of 69.00% (57.7%–77.8%) and 78.00% (68.6%–85.7%) (cutoff value of 8.5 × 103 μl), ESR with the sensitivity and specificity of 84.00% (75.3%–90.6%) and 99.00% (94.6%–100.0%) (cutoff value of 7.8), and CRP with the sensitivity and specificity of 52.00% (41.8%–62.1%) and 81.00% (71.9%–88.2%) (cutoff value of 1.9), respectively, had a significant prognostic value of AECOPD (P < 0.001). In addition to NLR had higher area under the curve (AUC) than PLR, WBC, and CRP. Therefore NLR had a better diagnostic value than the above three markers (P < 0.001). ESR also has higher AUC levels compared to PLR, WBC, and CRP and has a statistically better diagnostic value than them (P < 0.001), but did not differ significantly from ESR (difference between AUC: 0.02; P = 0.059). Conclusion: According to the results of the current study, NLR and PLR had a significant direct relationship with the two main markers of ESR and CRP, and both ratios had a significant prognostic value in AECOPD.