Globally, about one in four people develop a psychiatric disorder during their lifetime. Specifically, the lifetime prevalence of schizophrenia is about 0.48%, and schizophrenia can have detrimental effects on a patient's life. Therefore, estimating the economic burden of schizophrenia is important. We investigated the cost-of-illness trend of schizophrenia in South Korea from 2006 to 2016. The cost-of-illness trend was estimated from a societal perspective using a prevalence-based approach for direct costs and a human capital approach for indirect costs. We utilized information from the following sources: 1) National Health Insurance Service, 2) Korean Statistical Information Service, Statistics Korea, 3) the National Survey of Persons with Disabilities, 4) Budget and Fund Operation Plan, Ministry of Justice, 5) Budget and Fund Operation Plan, Ministry of Health and Welfare, and 6) annual reports from the National Mental Health Welfare Commission. Direct healthcare costs, direct non-healthcare costs, and indirect costs by sex and age group were calculated along with sensitivity analyses of the estimates. The cost-of-illness of schizophrenia in Korea steadily increased from 2006 to 2016, with most costs being indirect costs. Individuals in their 40s and 50s accounted for most of the direct and indirect costs. Among indirect costs, the costs due to unemployment were most prevalent. Our estimation implies that schizophrenia is associated with a vast cost-of-illness in Korea. Policymakers, researchers, and physicians need to put effort into shortening the duration of untreated psychosis, guide patients to receive community-care-based services rather than hospital-based services and empower lay people to learn about schizophrenia.