Purpose: There is currently no consensus on which protective strategy is most effective to prevent I-131 uptake in the thyroid during medical interventions in children. We aimed to collect the best available evidence to determine which pharmacological intervention is most effective in protecting the thyroid gland from damage by radioactive iodine (RAI). Methods: Literature searches were performed using PubMed, Embase, OLDMEDLINE, and the Cochrane Central Register of Controlled Trials. Only original studies were included (1950–2022). Studies comparing pharmacological prevention of the thyroid against RAI uptake or occurrence of hypothyroidism, thyroid nodule or thyroid cancer were included. Included studies were graded according to the Grading of Recommendations Assessment, Development and Evaluation considerations. Pharmacological interventions were compared for effectiveness on reduction of thyroidal intake or relevant clinical thyroidal outcomes. Results: Forty studies were included. Quality of included studies was low and many different outcome variables were used, making meta-analysis impossible. In 81% of studies, the pharmacological intervention could not prevent RAI uptake or thyroid damage. The administration of potassium iodide (KI) 1 h before exposure to RAI seemed most effective to reduce thyroidal uptake, however, hypothyroidism was reported in up to 64% as well as several cases of thyroid carcinoma. The combination of KI, thyroxine and thiamazole reduced RAI uptake and occurrence of hypothyroidism; yet, after follow-up of 9 years, still 50% of patients developed hypothyroidism. KI with potassium perchlorate showed hypothyroidism to occur in up to 12% of patients after short follow-up time. Conclusions: The lack of well-designed studies impairs making strong recommendations on the optimal way to prevent thyroid damage when using radioactive coupled ligands for medical interventions. To improve the protection of the thyroid against radiation damage by I-131, well-designed randomized clinical trials with sufficient follow-up time, comparing new protective strategies’ effects on valid and well-defined thyroid outcomes are needed.