Background Post-thyroidectomy hematoma (PH) is uncommon but may be a life-threatening complication. We explored perioperative risk factors for PH, with emphasis on perioperative hemodynamics, pain, and medications. Methods A retrospective case-control study was performed with matching for age, sex, and type of operation. Univariate and multivariate analyses were performed to identify independent risk factors. Results In 1780 thyroid surgeries, 22 cases of PH were detected (1.24%). Antithrombotic agent usage, numeric rating scale (NRS) of postoperative pain, and two or more doses of ketorolac postoperatively significantly differed between the two groups. Multiple regression analysis revealed all three variables were significant risk factors for PH (odds ratio = 55.23, 10.48, and 22.58, respectively). Perioperative hemodynamics did not affect PH. Conclusions Antithrombotic agent usage, postoperative pain, and two or more doses of ketorolac postoperatively were identified as independent risk factors for PH. Proper pain control and judicious usage of ketorolac are recommended.