Metal-organic frameworks are known to contain several types of defects within their crystalline structures. These defects are capable of inducing drastic changes to material properties, and successful engineering of these defects can significantly enhance the material performance. High-throughput computational screening of an experimental MOF database was conducted to identify 13 MOFs that show significantly improved methane storage capabilities with the introduction of linker vacancy defects. The candidates were identified by detecting the presence of methane inaccessible pores blocked away from the main adsorption channels. Then linker vacancy defects were emulated by exchanging the linker with appropriate modulators or solvents that would be used experimentally, which resulted in the connection and utilization of the previously inaccessible pores. Gas adsorption simulations of the defective MOFs showed significant enhancements in methane uptake, showing that rational defect engineering can be a novel and effective method to improve the performance of synthesized MOFs.