DNA-encoded library (DEL) technology employs DNA as unique molecular barcodes to rapidly construct and interrogate large-scale libraries, thereby facilitating the efficient identification of protein binders relative to conventional high-throughput screening (HTS). Nevertheless, the intrinsic sensitivity of DNA to harsh conditions, including elevated temperatures and strong acids, imposes significant limitations on the scope of DEL-compatible transformations. Further advancement of DEL-based drug discovery requires the development of additional DNA-compatible reaction conditions to substantially expand the accessible chemical space. Tetrahydrobenzopyrans and hexahydroquinoline scaffolds represent pharmacologically privileged motifs that exhibit a broad spectrum of biological activities. Herein, we report the implementation of on-DNA multicomponent reactions that enable the efficient synthesis of structurally diverse Tetrahydrobenzopyran and hexahydroquinoline derivatives, thereby enriching the scaffold diversity accessible within DEL platforms.