Objective This study investigated the changing trend in schistosome infection and liver fibrosis among residents in the Poyang Lake area, China, to evaluate the effectiveness of various control strategies at different phases. Methods The Xinhua Village of Lushan City, in Poyang Lake District, Jiangxi Province was set as the observation site for the study. The period of 1995—2019 was the mass chemotherapy phase, when permanent residents of the village over 5 years of age received chemotherapy yearly; the period of 2002—2009 was the targeting chemotherapy phase, when the villagers over 5 years of age were screened by serology, and those positives of serum antibody against were treated. In the infection source control phase covering 2010—2019, comprehensive measures including “closure of lake grass island and grazing prohibition/removing farm cattle (beef cattle)” were taken aiming at the control source of infection. In November or December every year, the modified Kato-Katz thick smear method was used to examine schistosome eggs in the fecal samples of villagers over than 5 years of age. From 1995 to 2003, fecal examination was performed with triplicate slide-reading/sample, while in 2004—2007, with two stool samples for 12 slide-reading (two fecal samples were collected from each participant at intervals of 3-5 days, and six slides were prepared from each sample); from 2008 to 2019, three samples for 27 slide-reading (three stool samples were collected from each participant at intervals of 3-5 days and nine slides were prepared from each sample). The fecal egg-positives were treated with praziquantel using either single oral dose once (40 mg/kg) or 2-day therapy (total dose 60 mg/kg, in three times a day for two days). In 1995—1998, 2000, 2002, 2007 and 2019, ultrasound scanning for liver parenchyma (liver fibrosis) was performed on residents who participated in stool examination. The liver parenchymal state was graded based on the renal parenchymal echo as the normal standard of reference. The four grades were grade 0, Ⅰ,Ⅱ and Ⅲ. The schistosome infection rate, infection intensity (eggs per gram feces, EPG), re-infection rate and liver parenchymal abnormality rate in residents were calculated for each year. The χ²-test was used for comparison of schistosome infection rates and re-infection rate between years. Pearson’s correlation analysis was used to compare the infection rate and infection intensity of each year, the infection rate in current year and next year, and the infection intensity of re-infected people in two years: previous and coming one. The association between the infection intensity before chemotherapy and the occurrence of re-infection in the following year was analyzed with Spearman’s correlation. Schistosomiasis liver parenchymal abnormality rates between years was compared through time series trend analysis. Results From 1995 to 2019, 309-978 villagers received fecal examination yearly. During the mass chemotherapy phase, the schistosome infection rate decreased from 17.89% (175/978) (95%CI: 15.49%-20.29%) in 1995 to 5.79% (50/864) (95%CI: 4.23%-7.34%) in 2001, with a decrease by 67.64%, and the difference between years was statistically significant (χ² = 197.752, P < 0.01). The infection rate in targeting chemotherapy phase showed increasing trend from 5.13% (40/780) (95%CI: 3.58%-6.68%) in 2002 to 7.97% (65/816) (95%CI: 6.11%-9.83%) in 2009, and the changes between years was statistically significant (χ² = 39.823, P < 0.01). In the infection source control phase, the infection rate declined year by year that from 3.30% (28/849) (95% CI: 2.10%-4.50%) in 2010 to 0 (0/475) in 2019. During the mass chemotherapy period, the average EPG in infected villagers was between 23.73 and 89.79, and peaked in 1995 (89.79) and 1998 (85.33). During the targeting chemotherapy phase, the average EPG in the infected maintained at 12.20-38.11. During the infection source control phase, the average EPG the infected was 44.19 in 2016, and that in all other years was lower than 20. Annually, the average EPG of the infected was in accordance with the change of infection rate (r = 0.784, P < 0.01). The re-infection rate in residents in 1996—2011 was 4.29%-38.46%, and the difference between years was statistically significant (χ² = 48.202, P < 0.01). The number of infected residents reduced after 2012, but re-infection occurred in 2017; the infection rate in villagers was uncorrelated with the re-infection (r = 0.245, P > 0.05); the infection intensity of re-infected villagers showed no correlation between two years of before and after; upon the EPG in infected villagers in that year was ≥ 10%, the infection intensity was correlated with re-infected occurrence in following year (r = 0.516, P < 0.01). Ultrasonography screening revealed that in 1995 to 1998, 2000, 2002, 2007 and 2019, the abnormality rate of liver parenchyma in residents ranging from 34.90% to 57.15%, with a median value of 50.36%, which was lowest in 1995, 34.90% (335/960), among them the lowest rate was found in 1995, the highest in 1998; the abnormality rate exceeded 50% in 1997, 1998, 2000 and 2007. No significant change in liver parenchyma grade Ⅰ was observed between years among residents with schistosomiasis (R² = 0.032, F = 0.019, P > 0.05); whereas grade Ⅱ and grade Ⅲ showed an increasing trend each year (R² = 0.397, 0.493; F = 7.367, 7.774; P < 0.05). Of the examinees with liver parenchyma abnormality, 204 received ultrasonography in 1995, 2007 and 2019. Compared to 1995, found in 2019, 24.51% (50/204) cases with liver fibrosis appeared improved; 29.90% (61/204) cases showed liver fibrosis remained in advancing; the fact of improvement or advancing of liver fibrosis was uncorrelated with the infection intensity (R² = 0.173, 0.365; F = 1.233, 2.174; P > 0.05). During 1995—2019, the participants with schistosome infection history showed the fibrosis advancing rate (54.24%, 32/59) higher than the improving rate (16.95%, 10/59) (χ² = 17.892, P < 0.01). Conclusion Comprehensive control strategy based mainly on chemotherapy is difficult to control schistosome infection in residents regardless of low infection rate in villagers, re-infection may still occur. The comprehensive strategy mainly based on controlling source of infection can effectively control schistosomiasis transmission. Hepatic lesion in people infected with schistosome showed chronic process.