Advancing the frontier of material design, our innovative magnetic ionic covalent organic framework (MiCOF) masterfully overcomes traditional barriers in selective adsorption, pioneering new functionalities and surface engineering techniques to effectively target and mitigate the impacts of benzimidazoles (BZDs). In previous studies, the idea of designing magnetic nanomaterials through theoretical screening of ionic liquids has been successfully proposed. This work proposed a theoretical and practical design for MiCOFs, aimed at providing a sensitive, selective, rapid, and straightforward method for analyzing trace substances in complex biological matrices. In a gentle one-pot process, the surface of Fe3O4 was coated with covalent organic frameworks (COFs) layer, followed by the modification with amino acid ionic liquid (AAIL) through covalent radical polymerization, facilitated by the abundant unsaturated vinyl groups present. This resulted in MiCOFs (Fe3O4@COF-AAIL) with a stable structure. Compared to unmodified Fe3O4@COF, Fe3O4@COF-AAIL exhibited excellent adsorption selectivity for BZDs. This enhanced selectivity is primarily due to the strong hydrogen bonds and π-π interactions between AAIL and BZDs, aligning well with COSMO-RS theoretical screening predictions. The development of magnetic dispersive solid-phase extraction (MDSPE) enabled rapid processing of BZDs in plasma with low matrix effects (0.9–1.3). This study not only validates a robust framework for the selective separation of trace contaminants in complex biological matrices but also advances the design and application of MiCOFs, setting a new paradigm in material science that could transform the design of novel materials for specific tasks.