Schistosomiasis is a chronic parasitic disease that continues to be a pressing public health problem in many developing countries. The primary pathological damage from the disease is granuloma and fibrosis caused by egg aggregation, and early treatment can effectively prevent the occurrence of liver fibrosis. Therefore, it is very important to identify biomarkers that can be used for early diagnosis of Schistosoma japonicum infection. In this study, a label-free proteomics method was performed to observe the alteration of proteins before infection, 1 week, and 6 weeks after infection, as well as 5 weeks and 7 weeks after treatment. A total of 10 proteins derived from S. japonicum and 242 host-derived proteins were identified and quantified as significantly changed. Temporal analysis was carried out to further analyze potential biomarkers with coherent changes during infection and treatment. The results revealed biological process changes in serum proteins compared to infection and treatment groups, which implicated receptor-mediated endocytosis, inflammatory response, and acute-phase response such as Mannan binding lectin serine peptidase 1, immunoglobulin, and phosphoglycerate mutase. These findings offer guidance for in-depth analysis of potential biomarkers of Schistosomiasis, host protein, and early diagnosis of S. japonica and its pathogenesis.