Metastatic colorectal cancer (mCRC) represents the advanced stage of colorectal cancer progression. Treatment options are diverse, but patient prognosis is generally poor. The epidermal growth factor receptor (EGFR) signaling pathway plays a central role in the development of mCRC, involving multiple key molecules. Abnormal activation of EGFR is closely related to tumor growth, metastasis, and treatment resistance. Therefore, EGFR-targeted therapy is crucial for mCRC, but treatment resistance often leads to therapy failure, and the molecular mechanisms are complex. Here, the authors review the molecular mechanisms related to anti-EGFR treatment resistance in mCRC and the progress in intervention studies, providing a reference for a deeper understanding of the mechanisms of anti-EGFR resistance and the optimization of treatment strategies.