Purpose: The exact link between cognitive impairment (CI) and chronic obstructive pulmonary disease (COPD) is still limited. Thus, we aim to find the relationship and interaction of quantitative CT (QCT), lung function, HIF-1α, and clinical factors with the development of CI among COPD patients. Patients and Methods: A cross-sectional multicentre study was conducted from January 2022 to December 2023. We collected clinical data, spirometry, CT images, and venous blood samples from 114 COPD participants. Cognitive impairment assessment using the Montreal Cognitive Assessment Indonesian version (MoCA-Ina) with a cutoff value 26. The QCT analysis consists of lung density, airway wall thickness, pulmonary artery-to-aorta ratio (PA:A), and pectoralis muscles using 3D Slicer software. Serum HIF-1α analysis was performed using ELISA. Results: We found significant differences between %LAA−950, age, COPD duration, BMI, FEV1 pp, and FEV1 /FVC among GOLD grades I–IV. Only education duration was found to correlate with CI (r = 0.40; < 0.001). We found no significant difference in HIF-1α among GOLD grades (p = 0.149) and no correlation between HIF-1α and CI (p = 0.105). From multiple linear regression, we observed that the MoCA-Ina score was influenced mainly by %LAA−950 (p = 0.02) and education duration (p = 0.01). The path analysis model showed both %LAA and education duration directly and indirectly through FEV1 pp contributing to CI. Conclusion: We conclude that the utilization of QCT parameters is beneficial as it can identify abnormalities and contribute to the development of CI, indicating its potential utility in clinical decision-making. The MoCA-Ina score in COPD is mainly affected by %LAA−950 and education duration. Contrary to expectations, this study concludes that HIF-1α does not affect CI among COPD patients. © 2024 Simargi et al.