Epidermal growth factor receptor (EGFR) serves as a key therapeutic target for solid tumors such as non-small cell lung cancer (NSCLC), where its mutations and overexpression often lead to sustained activation of oncogenic signaling pathways. This study represents a comparative analysis of multiple targeted chimeric degradation technologies targeting EGFR allosteric sites, aiming to provide clearer guidance for the future development of allosteric EGFR degraders. Results demonstrate that the VHL-based PROTAC compound III-4 exhibits optimal degradation activity against EGFRWT and EGFRDel19, degrading approximately 76% and 72% at 0.1 μM, respectively, with degradation partially dependent on the ubiquitin-proteasome pathway. For degrading the acquired resistance mutant EGFRL858R/T790M, CRBN-based PROTAC compounds II-3 and II-5 demonstrated significant efficacy (approximately 60% degradation at 0.1 μM) and effectively inhibited H1975 cell proliferation (IC50 values of 23.32 μM and 14.31 μM, respectively). In contrast, AUTAC and HyT-type compounds exhibited overall weaker degradation activity, relying on the autophagy-lysosomal pathway and proteasome pathway, respectively. Physicochemical analysis indicated that PROTAC compounds exhibited cLogP and polar surface area (PSA) values closer to the ideal range, potentially contributing to their cellular permeability and degradation activity. In summary, this study represents a deepened and extended investigation built directly on previous seminal work, aiming to provide clearer guidance for the future development of allosteric EGFR degraders.