Epidermal growth factor receptor (EGFR)-targeted therapeutics, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), have achieved clinical success but are limited by drug resistance and off-target toxicity. Herein, self-assembling peptide-derived PROTAC nanoparticles (NanoTACs) engineered for effective degradation of both wild-type and mutant EGFR for cancer therapy is reported. The NanoTACs are constructed from three peptide components: EGFR-binding peptide (EHGAMEI), a self-assembling peptide linker (FF), and an E3 ligase recruiting peptide (ALAPYIP). Through the hydrophobic interaction and π-π stacking, self-assembling peptide-derived PROTACs formed uniform spherical nanoparticles with an average diameter of 144 nm under aqueous conditions. In vitro, NanoTACs effectively eliminated both wild-type and L858R/T790M-mutant EGFR in cancer cells through direct lysosomal degradation and PROTAC-driven proteasomal degradation. In vivo, NanoTACs exhibited 2.24-fold higher tumor-targeting efficiency than free EGFR-binding peptide via the enhanced permeability and retention (EPR) effect and EGFR-mediated active targeting. In colon and lung tumor models, NanoTACs suppressed tumor growth by 88.3%, achieved 95% degradation of wild-type and 80% of mutant EGFR, and induced extensive apoptosis without systemic toxicity. These findings established NanoTACs as a promising EGFR-targeted platform to overcome drug resistance to mAbs and TKIs by enabling effective degradation of wild-type and mutant EGFR in heterogeneous cancers.