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Background: There is a continuous decline in the prevalence of schistosomiasis and the number of Schistosoma japonicum infections in humans and livestock in China. However, there are a large number of factors that have not been resolved and which may contribute to future transmission of schistosomiasis. These include a range of sources for S. japonicum infection, difficulty in management of S. japonicum sources of infection, frequent emergence and re-emergence of Oncomelania hupensis snail habitats, and the problematic elimination of snail habitats. These factors challenge progress towards the elimination of schistosomiasis in China.Methods: Based on multi-stage continuous downscaling of sentinel monitoring, county-based schistosomiasis surveillance data were captured from the national schistosomiasis surveillance sites of China from 2005 to 2019. The data included S. japonicum infections in humans, livestock, and O. hupensis. The spatio-temporal trends for schistosomiasis were detected using a Joinpoint regression model, with a standard deviational ellipse (SDE) tool, which determined the central tendency and dispersion in spatial distribution of schistosomiasis. Further, spatio-temporal clusters of S. japonicum infections in humans, livestock, and O. hupensis were evaluated by Poisson model. Results: The prevalence of S. japonicum human infections was reduced from 2.06% to zero based on the national schistosomiasis surveillance sites of China during the period from 2005 to 2019, with a reduction from 9.42% to zero for the prevalence of S. japonicum infections in livestock, and from 0.26% to zero for the prevalence of S. japonicum infections in O. hupensis. The decline in prevalence of S. japonicum infections in humans, livestock, and O. hupensis was statistically significant from 2005 to 2019 (P < 0.01). There was an exception to the decline in S. japonicum infections in livestock during the period from 2008 to 2012. Using an SDE tool, schistosomiasis-affected regions were reduced yearly from 2005 to 2014 in the endemic provinces of Hunan, Hubei, Jiangxi, and Anhui, as well as in the Poyang and Dongting Lake regions. Poisson model revealed 11 clusters of S. japonicum human infections, six clusters of S. japonicum infections in livestock, and nine clusters of S. japonicum infections in O. hupensis. The clusters of human infection were found to be highly consistent with clusters of S. japonicum infections in livestock and O. hupensis. These clusters were in the five provinces of Hunan, Hubei, Jiangxi, Anhui, and Jiangsu, as well as along the middle and lower reaches of the Yangtze River. Humans, livestock, and O. hupensis infections with S. japonicum were mainly concentrated in the north of the Hunan Province, south of the Hubei Province, north of the Jiangxi Province, and southwestern portion of Anhui Province. In the two mountainous provinces of Sichuan and Yunnan; human, livestock, and O. hupensis infections with S. japonicum were mainly concentrated in the northwestern portion of the Yunnan Province, the Daliangshan area in the south of Sichuan Province, and the hilly regions in the middle of Sichuan Province. Conclusions: This study demonstrate a significant spatio-temporal heterogeneity of schistosomiasis in China. A remarkable decline in endemic schistosomiasis was observed between 2005 and 2019. However, there continues to be a long-term risk of schistosomiasis transmission in local areas, with high-risk areas primarily located in the Poyang Lake and Dongting Lake regions, with frequent acute S. japonicum infections. Using a One Health approach, further reinforcement of an integrated schistosomiasis control strategy, with an emphasis on the sources of S. japonicum infection, is required to facilitate the elimination of schistosomiasis in China by 2030.