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Background Hospitalization burden related to hepatitis C virus (HCV) infection is substantial. We sought to describe temporal trends in hospitalization rates before and after release of direct-acting antiviral (DAA) agents. Methods We analyzed 2000–2019 data from adults aged ≥18 years in the National Inpatient Sample. Hospitalizations were HCV-related if (1) hepatitis C was the primary diagnosis, or (2) hepatitis C was any secondary diagnosis with a liver-related primary diagnosis. We analyzed characteristics of HCV-related hospitalizations nationally and examined trends in age-adjusted hospitalization rates. Results During 2000–2019, there were an estimated 1 286 397 HCV-related hospitalizations in the United States. The annual age-adjusted hospitalization rate was lowest in 2019 (18.7/100 000 population) and highest in 2012 (29.6/100 000 population). Most hospitalizations occurred among persons aged 45–64 years (71.8%), males (67.1%), White non-Hispanic persons (60.5%), and Medicaid/Medicare recipients (64.0%). The national age-adjusted hospitalization rate increased during 2000–2003 (annual percentage change [APC], 9.4%; P <.001) and 2003–2013 (APC, 1.8%; P <.001) before decreasing during 2013–2019 (APC, −7.6%; P <.001). Comparing 2000 to 2019, the largest increases in hospitalization rates occurred among persons aged 55–64 years (132.9%), Medicaid recipients (41.6%), and Black non-Hispanic persons (22.3%). Conclusions Although multiple factors likely contributed, overall HCV-related hospitalization rates declined steadily after 2013, coinciding with the release of DAAs. However, the declines were not observed equally among age, race/ethnicity, or insurance categories. Expanded access to DAA treatment is needed, particularly among Medicaid and Medicare recipients, to reduce disparities and morbidity and eliminate hepatitis C as a public health threat. [ABSTRACT FROM AUTHOR]