Treatment with immune checkpoint inhibitors has improved the prognosis of solid tumors. However, immune-related adverse events (IRAEs), including exacerbation of pre-existing autoimmune disease, are common and have become more frequent with combination therapy. The literature is scanty regarding reports of the use of combination immune checkpoint therapy in patients with pre-existing autoimmune hypothyroidism. We report a case of a man with a history of hypothyroidism, who developed transient thyroiditis, characterized by a thyrotoxic phase followed by a severe hypothyroid phase soon after receiving combination therapy (nivolumab and ipilimumab) for the treatment of a malignant pleural mesothelioma. He had been on a stable low dose of levothyroxine for 12 years prior to this episode. His levothyroxine requirement markedly increased soon after the episode of immune checkpoint inhibitor-induced thyroiditis. Immune checkpoint inhibitors can cause destructive thyroiditis followed by exacerbation of hypothyroidism in patients with pre-existing autoimmune hypothyroidism, such that patients end up on a higher dose of levothyroxine. This case will add to the growing literature regarding thyroid IRAEs associated with the use of immune checkpoint inhibitors in patients with pre-existing autoimmune thyroid disease.