<p>Colorectal cancer (CRC) is a severe health risk, and while Cetuximab is a key treatment, resistance due to KRAS mutations poses a challenge. The role of ALKBH5, often overexpressed in cancers, in KRAS-mutated CRC and its resistance to Cetuximab is not yet fully understood. This research initiates an inquiry from both cellular and animal experimental perspectives, investigating the potential of ALKBH5 to confer resistance to Cetuximab in colorectal cancer cells harboring KRAS mutations. We investigated ALKBH5 expression in clinical samples of CRC with varying responses to Cetuximab and KRAS statuses. Drug-resistant cell lines were developed using incremental drug concentrations, and the effects of ALKBH5 modulation on cell viability and proliferation were assessed using CCK-8 and clonogenic assays. The in vivo impact of ALKBH5 on drug resistance in KRAS-mutant cells was explored. Transcriptome sequencing of ALKBH5 knockdown cells pinpointed genes linked to Cetuximab resistance. We also examined ALKBH5’s regulation of FOXM1 m⁶A methylation with dual-luciferase and MeRIP assays and conducted FOXM1 functional reversal studies, alongside Western blot analysis of Wnt/β-catenin pathway proteins. Elevated ALKBH5 expression is positively correlated with Cetuximab resistance in KRAS-mutant CRC. ALKBH5 confers Cetuximab resistance to CRC cells in a KRAS-mutation-dependent manner in vitro and in vivo. ALKBH5 regulates FOXM1 expression through m⁶A demethylation, and FOXM1 can reverse Cetuximab resistance in ALKBH5-modulated KRAS-mutated CRC cells. Additionally, FOXM1 influences the sensitivity of KRAS-mutant tumors to Cetuximab by regulating the Wnt/β-catenin pathway. ALKBH5 plays a crucial role in the resistance of KRAS-mutant CRC to Cetuximab by inhibiting the m⁶A RNA methylation of FOXM1 and suppressing the activation of the Wnt/β-catenin signaling pathway.</p>