•A unified simulation methodology offers guidance for selecting MOFs for biogas purification.•The efficiency of CH4/CO2 separation rely on the initial humidity levels of the biogas.•Hydrophilic MOFs exposed to water vapor experience a decrease in performance. The adsorption of gases in nanopores represents a promising engineering tool applicable for gas storage and separation. This study provides a comprehensive evaluation of metal–organic frameworks (MOFs) for biogas purification, with a specific focus on their performance under humid conditions. Beginning with 22 structures identified in the literature as potential top sorbents, we employ numerical simulations of adsorption and kinetic selectivity to identify the best-performing MOFs. The research reveals that the presence of water significantly impacts the biogas separation process due to water clustering, which notably affects CO2 adsorption. The simulations also indicate variations in regenerability and selective adsorption among the initially selected MOFs in wet conditions. These findings underscore the effectiveness of high-throughput numerical screening in identifying materials with specific properties and ensuring stable performance under varying environmental conditions.