In this study, the diagnostic value of Schistosoma japonicum cathepsin B (SjCatB) was evaluated as an antigen for the early detection of S. japonicum infection. SjCatB is a key protease used by the cercaria to penetrate the intact skin of the host for transdermal infection. The early exposure of the host’s immune system to this enzyme may elicit early production of antibodies against this molecule. Therefore, the recombinant SjCatB (rSjCatB) was expressed in Escherichia coli with N-terminal 6xHis-tag. rSjCatB was tested for its performance as a diagnostic antigen using indirect enzyme-linked immunosorbent assay (ELISA) with sera from experimentally infected mice collected at > 8 weeks post-infection. Showing 100% sensitivity and 95.0% specificity in the ELISA, rSjCatB was then evaluated with sera from experimentally infected mice collected at 1–7 weeks post-infection to determine how early the antibodies can be detected. Results showed that as early as 6 weeks post-infection, 2 of the 3 infected mice were found to be positive with the antibodies against SjCatB. Furthermore, the potential of the recombinant antigen in detecting human schistosomiasis was evaluated with archived serum samples collected from individuals who had been diagnosed with S. japonicum infection by stool examination. Results showed 86.7% sensitivity and 96.7% specificity suggesting its high diagnostic potential for human schistosomiasis. In addition, SjCatB showed minimal cross-reaction with the sera collected from patients with other parasitic diseases. In conclusion, the results of this study suggest that SjCatB will be useful in the development of a sensitive and specific early detection test for S. japonicum infection.