BRAF V600E mutation in thyroid malignancies is associated with an aggressive phenotype with more rapid tumor growth and higher mortality. V600E is a driver mutation in the BRAF proto-oncogene, where valine (V) is substituted by glutamic acid (E) at amino acid 600. New chemotherapeutic agents targeting the mitogen-activated protein kinase (MAPK) pathway, including direct BRAF inhibitors, have become available and are increasingly used in various advanced thyroid malignancies. These agents are associated with various rare neurological adverse effects. We present a case of Guillain-Barre syndrome (GBS) secondary to dabrafenib and trametinib therapy for the management of anaplastic thyroid carcinoma. A few cases of GBS have been reported previously with the use of these agents in the treatment of melanoma. To our knowledge, this is the first case of GBS with the use of dabrafenib and trametinib for advanced thyroid malignancy. The knowledge of this rare, potentially life-threatening condition is important for clinicians to know, given the increased use of these agents in managing advanced thyroid malignancies.