Background <p>While combination BRAF and MEK inhibitor treatment in <i>BRAF</i>^<i>V600E</i>-mutant cancers results in a response, treatment resistance and toxicity are common. Ferroptosis is an iron-dependent form of non-apoptotic cell death. BRAF inhibition has been associated with increased sensitivity to ferroptosis that is dependent on Glutathione Peroxidase 4 (GPX4).</p> Methods <p>In vitro, ex vivo, and in vivo models of anaplastic thyroid cancer (ATC) were used to evaluate the anticancer activity of combination BRAF inhibition and ferroptosis induction.</p> Results <p>Targeting key regulators of ferroptosis—GPX4, using RSL3 and ML162, and system X_c⁻, using erastin—induced significant cell death in all ATC cell lines. Combination of dabrafenib and RSL3 synergistically increased cell death in <i>BRAF</i>^<i>V600E</i>-mutant ATC cells, and significantly inhibited colony formation. Mechanistically, lipid peroxidation, reactive oxygen species levels, and intracellular Fe²⁺ increased significantly with combination treatment compared with each agent alone. Analysis of cell membrane iron importers and exporters showed significantly lower expression of ferroportin-1 (an iron exporter), suggesting the synergistic anticancer activity was due to increased iron accumulation and oxidative stress, leading to enhanced ferroptotic cell death. <i>BRAF</i>^<i>V600E</i>-mutant ATC cell spheroids showed synergistic cell death with dabrafenib and RSL3 treatment. In vivo, combination dabrafenib and ferroptosis induction (by targeting GPX4 using C18, and system X_c⁻ with IKE) significantly inhibited tumor growth in an orthotopic ATC mouse model. Additionally, dabrafenib-resistant <i>BRAF</i>^<i>V600E</i>-mutant ATC cells were more sensitive to ferroptosis induction than parental cells.</p> Conclusions <p>Dual targeting of BRAFV600E and ferroptosis results in synergistic anticancer activity and overcomes resistance to BRAF inhibition.</p>