ObjectivesAs global efforts continue toward the target of eliminating viral hepatitis by 2030, the emergence of acute hepatitis of unspecified aetiology (HUA) remains a concern. This study assesses the overall trends and changes in spatiotemporal patterns in HUA in China from 2004 to 2021.MethodsWe extracted the incidence and mortality rates of HUA from the Public Health Data Center, the official website of the National Health Commission of the People’s Republic of China, and the National Notifiable Infectious Disease Surveillance System from 2004 to 2021. We used R software, ArcGIS, Moran’s statistical analysis, and joinpoint regression to examine the spatiotemporal patterns and annual percentage change in incidence and mortality of the HUA across China.ResultsFrom 2004 to 2021, a total of 707,559 cases of HUA have been diagnosed, including 636 deaths. The proportion of HUA in viral hepatitis gradually decreased from 7.55% in 2004 to 0.72% in 2021. The annual incidence of HUA decreased sharply from 6.6957 per 100,000 population in 2004 to 0.6302 per 100,000 population in 2021, with an average annual percentage change (APC) reduction of −13.1% (p< 0.001). The same result was seen in the mortality (APC, −22.14%, from 0.0089/100,000 in 2004 to 0.0002/100,000 in 2021,p< 0.001). All Chinese provinces saw a decline in incidence and mortality. Longitudinal analysis identified the age distribution in the incidence and mortality of HUA did not change and was highest in persons aged 15–59 years, accounting for 70% of all reported cases. During the COVID-19 pandemic, no significant increase was seen in pediatric HUA cases in China.ConclusionChina is experiencing an unprecedented decline in HUA, with the lowest incidence and mortality for 18 years. However, it is still important to sensitively monitor the overall trends of HUA and further improve HUA public health policy and practice in China.