The sodium iodide symporter (NIS) is required for iodide uptake which facilitates thyroid hormone biosynthesis. NIS has been exploited for over 75 years in ablative radioiodine (RAI) treatment of thyroid cancer where its ability to transport radioisotopes depends on its localization to the plasma membrane. The advent of NIS-based in vivo imaging and theranostic strategies in other malignancies and disease modalities has recently increased the clinical importance of NIS. However, NIS trafficking remains ill-defined. Here, we employed tandem mass spectrometry followed by co-immunoprecipitation and proximity ligation assays to identify and validate two key nodes - ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP) - controlling NIS trafficking. Using cell surface biotinylation assays and highly inclined and laminated optical sheet microscopy we demonstrated that ARF4 enhanced NIS vesicular trafficking from the Golgi to the plasma membrane, whereas VCP - a principal component of ER-associated degradation - governed NIS proteolysis. Gene expression analysis indicated VCP expression was particularly induced in aggressive thyroid cancers and in patients who had poorer outcomes following RAI treatment. Two re-purposed Food and Drug Administration (FDA)-approved VCP inhibitors abrogated VCP-mediated repression of NIS function resulting in significantly increased NIS at the cell surface and markedly increased RAI uptake in mouse and human thyroid models. Collectively, these discoveries delineate NIS trafficking and highlight the new possibility of systemically enhancing RAI therapy in patients using FDA-approved drugs.