HYPOTHESIS: Thyroidectomy is a procedure for treatment of thyroid lesions. A common adverse effect is voice change that impairs the patient's well-being. This study aimed to investigate the effect of Rosuvastatin and Calcitriol on preventing voice change after thyroidectomy. STUDY DESIGN: This is a parallel, single-blinded, block-randomized controlled trial in a tertiary medical center in southern Iran, Shiraz. METHODS: Adult patients scheduled for total thyroidectomy in 2023 were randomly assigned to one of three groups: Rosuvastatin, Rosuvastatin and Calcitriol, or no anti-inflammatory medication starting 14 days before surgery. The surgeon and the individuals who collected the data were blinded to the allocated groups. Voice change was evaluated 2 weeks after surgery. Written consent was obtained. RESULTS: In total, 177 patients were included in this study, 29 (16.4%) males and 148 (83.6%) females. In total, 66 (37.3%) received Rosuvastatin and Calcitriol, 54 (30.5%) received only Rosuvastatin, and 57 (32.2%) did not receive any medication 2 weeks prior to surgery. Consequently, 123 (69.5%), 42 (23.7%), and 12 (6.8%) had minimal, moderate, and severe voice disorder. Voice change was not significantly different among patients who received Rosuvastatin and Calcitriol and Rosuvastatin alone compared with the group with no drugs (P value = 0.199 and 0.646, respectively). CONCLUSION: This study suggests that there was no difference in the severity of voice change or in the components of the Voice Handicap Index between patients who received medication and those who did not. Further investigations are warranted to optimize patients' outcomes and quality of life after thyroidectomy. TRIAL REGISTRATION NUMBER: IRCT20230711058741N1.