Epidermal Growth Factor Receptor (EGFR) targeted therapies have yielded variable results in clinical trials for breast and head and neck cancers, despite EGFR overexpression in these malignancies. Primary resistance to these therapies is common, with secondary resistance often arising due to the overexpression of other receptor tyrosine kinases (RTKs) and increased downstream signaling from these RTKs. Additionally, non-RTK-driven mechanisms also contribute to anti-EGFR therapy resistance. This review highlights the role of AXL, MET, and RON families of RTKs in tumor progression and resistance to anti-EGFR therapies, focusing on breast and head and neck cancers. In breast cancer, the review discusses the intricate relationship between EGFR expression and therapeutic outcomes, emphasizing the challenges and potential strategies for enhancing EGFR-targeted treatments. It details how EGFR inhibition affects tumor progression and survival in head and neck cancer, noting that small molecule inhibitors and monoclonal antibodies, such as cetuximab, can lead to trans-activation of other RTKs. The review further explores non-RTK-driven resistance mechanisms in breast cancer, including EGFR activation through EGF-related ligands, nuclear localization of EGFR, and the overexpression of resistance-conferring proteins. In head and neck cancer, resistance is also mediated by TLR4-MyD88 signaling activation, loss of tumor suppressor genes like PTEN, activating mutations in PI3K, and involvement of STAT3. By synthesizing current insights on both RTK and non-RTK mediated resistance against anti-EGFR therapies, this review aims to guide future research and improve therapeutic strategies for these cancers.