<p>Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, with <i>KRAS</i> mutations playing a significant role in its tumorigenesis. Among the <i>KRAS</i> variants, the G13D mutation is associated with poor prognosis and distinctive biological behaviors. This study focuses on the role of HER2, a critical prognostic and predictive biomarker, in modulating the unique characteristics of <i>KRAS</i>^<i>G13D</i>-mutated CRCs. We identified a novel transcriptional regulatory network involving HER2, ELF3, and KRAS, with ELF3 acting as a key transcription factor (TF) that regulates KRAS expression under conditions of HER2 overexpression. Our findings reveal that this HER2-ELF3-KRAS axis is exclusively activated in <i>KRAS</i>^<i>G13D</i>, driving aggressive oncogenic features and conferring resistance to cetuximab (CTX) therapy. Through comprehensive analysis of gene expression profiles, we demonstrated that HER2 is a crucial therapeutic target specifically for <i>KRAS</i>^<i>G13D</i> CRCs. To explore this further, we introduced YK1, a small molecule inhibitor designed to disrupt the ELF3-MED23 interaction, leading to the transcriptional downregulation of HER2 and KRAS. This intervention significantly attenuated the HER2-ELF3-KRAS axis, sensitizing <i>KRAS</i>^<i>G13D</i> CRCs to CTX and reducing their tumorigenic potential by inhibiting the epithelial-to-mesenchymal transition process. Our study underscores the importance of HER2 as a key determinant in the unique biological characteristics of <i>KRAS</i>^<i>G13D</i> CRCs and highlights the therapeutic potential of targeting the HER2-ELF3-KRAS axis. By presenting YK1 as a novel pharmacological approach, we provide a promising strategy for developing tailored interventions for <i>KRAS</i>^<i>G13D</i> CRCs, contributing to the ongoing efforts in precision medicine for CRCs.</p> Graphical Abstract <p></p>