Summary Objective Post‐thyroidectomy hypocalcaemia is a significant cause of morbidity and prolonged hospitalization, usually due to transient parathyroid gland damage, treated with calcium and vitamin D supplementation. We present a randomized, double‐blinded placebo‐controlled trial of preoperative loading with high‐dose cholecalciferol (300 000 IU) to reduce post‐thyroidectomy hypocalcaemia. Patients and Measurements Patients (n = 160) presenting for thyroidectomy at tertiary hospitals were randomized 1:1 to cholecalciferol (300 000 IU) or placebo 7 days prior to thyroidectomy. Ten patients withdrew prior to surgery. The primary outcome was post‐operative hypocalcaemia (corrected calcium <2.1 mmol/L in first 180 days). Results The study included 150 patients undergoing thyroidectomy for Graves’ disease (31%), malignancy (20%) and goitre (49%). Mean pre‐enrolment vitamin D was 72 ± 26 nmol/L. Postoperative hypocalcaemia occurred in 21/72 (29%) assigned to cholecalciferol and 30/78 (38%) participants assigned to placebo (P = 0.23). There were no differences in secondary end‐points between groups. In pre‐specified stratification, baseline vitamin D status did not predict hypocalcaemia, although most individuals were vitamin D replete at baseline. Post‐hoc stratification by day 1 parathyroid hormone (PTH) (<10 pg/mL, low vs ≥10 pg/mL, normal) was explored due to highly divergent rates of hypocalcaemia in these groups. Using a Cox regression model, the hazard ratio for hypocalcaemia in the cholecalciferol group was 0.56 (95%CI 0.32‐0.98, P = 0.04) after stratification for Day 1 PTH. Further clinical benefits were observed in these subgroups. Conclusions Pre‐thyroidectomy treatment with high‐dose cholecalciferol did not reduce the overall rate of hypocalcaemia following thyroidectomy. In subgroups stratified by day 1 PTH status, improved clinical outcomes were noted.