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Background: The number of thyroidectomies in South Korea has been increasing rapidly due to extensive checkups for thyroid cancer. However, few studies have examined the association between thyroidectomy and major depressive disorder (MDD). We investigated the association between thyroidectomy and the risk of MDD. Methods: A population-based electronic medical records database from South Korea was used to identify 187,176 individuals who underwent partial or total thyroidectomy between 2009 and 2016. A self-controlled case series design and Cox regression analyses were used to identify risk factors for MDD. Results: Among the 187,176 individuals who underwent thyroidectomy, 16,744 (8.9%) were diagnosed with MDD during the observation period. Of those, 3837 (22.9%) underwent partial thyroidectomy and 12,907 (77.1%) underwent total thyroidectomy. An elevated MDD risk was found during the one-year period before thyroidectomy, with incidence rate ratios (IRRs) of 1.29 ([95% confidence interval [CI] 1.18–1.41], p < 0.0001) for subjects with partial thyroidectomy and 1.27 ([95% CI 1.21–1.33], p < 0.0001) for subjects with total thyroidectomy. After total thyroidectomy, the IRR increased for 31–60 days (IRR 1.81; [95% CI 1.59–2.06], p < 0.0001) and remained elevated for up to 540 days, whereas after partial thyroidectomy, the IRR increased for 31–60 days (IRR 1.68; [95% CI 1.32–2.13], p < 0.0001) but returned to baseline levels after 270 days. Total thyroidectomy was associated with a prolonged risk of MDD compared with partial thyroidectomy in patients with cancer, which was different from the results in patients without cancer. Conclusion: The incidence of MDD increased in the period immediately after thyroidectomy and remained high for one to two years. This study highlights the importance of relatively long-term regular psychiatric assessments in patients who undergo partial or total thyroidectomy. [ABSTRACT FROM AUTHOR]