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Achieving optimal therapeutic efficacy in colorectal cancer (CRC) remains challenging, highlighting the need for novel treatment strategies. This study evaluated whether radiofrequency (RF) hyperthermia enhances the anticancer effects of sunitinib malate and a newly synthesized tyrosine kinase (TK) inhibitor (compound 4). HCT116 CRC cells and BEAS-2B normal epithelial cells were treated with increasing concentrations of both agents in the presence or absence of RF exposure using a mobile RF device. Cell viability and death were assessed by MTT assay and flow cytometry (Annexin V/PI). RF exposure was associated with reduced viability and increased cell death in HCT116 cells (p < 0.05). Flow cytometric analysis confirmed that RF exposure may contribute to the observed reduction in viability. Notably, the findings suggest a possible beneficial contribution of RF hyperthermia to the observed cytotoxic effects, particularly near the IC50 concentration. In contrast, BEAS-2B cells maintained high viability with no significant changes (p > 0.05). These findings suggest that RF exposure may contribute to the observed cytotoxic responses in CRC cells while exerting limited effects on non-malignant cells, suggesting a promising strategy for targeted therapy.