For >75 years radioiodide (RAI) has been used to target metastases and safely and specifically destroy remaining thyroid cancer cells post-surgery. Despite this, activity of the sodium iodide symporter (NIS) – the sole conduit for cellular iodide uptake – is diminished in 25-50% of thyroid cancers, limiting adequate RAI uptake for effective therapeutic ablation. Thus, identifying targetable processes that govern NIS function is urgently needed to enhance RAI uptake and diminish recurrent thyroid cancer. Here we utilized the mutated yellow fluorescent protein (YFP) as a surrogate biosensor of intracellular iodide and screened 1200 drugs (95% FDA approved), allowing us to identify putative candidate drugs which increased iodide uptake. Categorization revealed a high proportion of drugs that modulate the proteostasis network (20/50 top candidate drugs; 40%), including key processes in protein homeostasis such as endoplasmic reticulum-associated protein degradation (ERAD) and autophagy. Secondary screening validated the activity of proteostasis modulators in enhancing iodide uptake after ranking 73 compounds based on their pharmacologic properties (AUC, EC50) and specificity of response (NIS+ve vs NIS-ve YFP-thyroid cells) at ten different drug doses (0.1-50 uM). Dose-dependent increases in 125I uptake were apparent across multiple cancer cell models, as well as human primary thyrocytes, implying that proteostatic and related pathways are central to the innate control of NIS function. Subsequent mechanistic insight allowed us to evolve entirely novel combinatorial drug strategies, routinely leading to robust and significant > 5-fold increases in RAI uptake (all p < 0.001). Appraisal of TCGA to study the clinical relevance of proteostasis modulators identified significant dysregulation of 13 core proteostasis genes linked to recurrence in RAI-treated papillary thyroid cancer (PTC) compared to non-recurrent controls (all p < 0.05). Critically, a predictive risk model based on these 13 genes showed that RAI-treated PTC patients at high risk had a significantly worse prognosis than those at low risk [Hazard Ratio (HR) = 35.87, 95% CI 4.81-267.41; p < 0.001; n =137]. By comparison, there was no difference in the prognosis of non-RAI treated PTC patients stratified into risk groups. Moreover, after controlling for age, gender, disease stage, tumor stage and node status, multivariate analysis showed that the 13 proteostasis gene risk score classifier was the sole independent predictive factor for thyroid cancer recurrence (HR = 4.55, 95% CI 2.38-8.70; p < 0.001) in the entire TCGA cohort (n = 438). Whilst oncogene activation can suppress NIS expression and function, our study has identified new non-canonical pathways that govern radioiodide uptake. Collectively, we therefore propose a new model for the targetable steps of intracellular processing of NIS, with translatable potential to address the current lack of clinical options for patients treated with RAI who typically have poorer clinical outcomes.