Background Hypothyroidism has been independently associated with the development of several comorbidities and is known to increase complication rates in non-spinal surgeries. However, there are limited data regarding the effects of hypothyroidism in major spine surgery. Therefore, we present the largest retrospective analysis evaluating outcomes in hypothyroid patients undergoing spinal fusion. Methods A retrospective review of the National Inpatient Sample (NIS) from 2004-2014 was performed. Patients with an International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) procedure code indicating spinal fusion (81.04-81.08, 81.34-81.38, 81.0x, 81.3x) were included. Patients with an ICD-9-CM diagnosis code indicating hypothyroidism (244.x) were compared to those without. Cervical and lumbar fusions were evaluated independently. Significant covariates in univariable logistic regression were utilized to construct multivariable models to analyze the effect of hypothyroidism on perioperative morbidity and mortality. Results A total of 4,149,125 patients were identified, of which 9.4% were hypothyroid. Although, hypothyroid patients had a higher risk of hematologic complications (lumbar – odds ratio [OR] 1.176, p < 0.0001; cervical - OR 1.162, p < 0.0001), they exhibited decreased in-hospital mortality (lumbar - OR .643, p < 0.0001; cervical - OR .606, p < 0.0001). Hypothyroid lumbar fusion patients also demonstrated decreased rates of perioperative myocardial infarction (MI) (OR .851, p < 0.0001). All these results were independent of patient gender. Conclusions Hypothyroid patients undergoing spinal fusion demonstrated lower rates of inpatient mortality and, in lumbar fusions, also had lower rates of acute MI when compared to their euthyroid counterparts. This suggests that hypothyroidism may offer protection against all-cause mortality and may be cardioprotective in the postoperative period for lumbar spinal fusions independent of patient gender.