Thioredoxin peroxidases (TPxs) play an important role in maintaining redox homeostasis and in protecting organisms from the accumulation of toxic reactive oxygen species (ROS). In this study, we isolated the thioredoxin peroxidase-3 gene of Schistosoma japonicum, SjTPx-3. The open reading frame (ORF) of SjTPx-3 was 663 bp encoding 220 amino acids with a molecular weight of 24.99 kDa and an isoelectric point of 6.20. Quantitative real-time reverse transcription-polymerase chain reaction indicated that SjTPx-3 was expressed in all different stages of the parasites, with highest expression in 35-day-old worms. The ORF of SjTPx-3 was subcloned into pET-32a (+) vectors and expressed in Escherichia coli. Recombinant SjTPx-3 (rSjTPx-3) was expressed as a soluble protein with good antigenicity, as demonstrated by western blotting. Immunohistochemical analysis revealed that SjTPx-3 was mainly localized on the tegument of the parasites. Mice vaccinated with rSjTPx-3 had a 37.02% (P < 0.05) reduction in worm burden and 56.52% (P < 0.05) reduction in liver egg production compared with control, unvaccinated mice. Enzyme-linked immunosorbent assay analysis demonstrated that rSjTPx-3 could induce high levels of anti-rSjTPx-3-specific IgG, IgG1, and IgG2a antibodies. Characteristic Th1 and Th2 immune response cytokines were detected by flow cytometry and were increased by rSjTPx-3. Taken together, these results suggest that SjTPx-3 is an antioxidant enzyme responsible for protecting S. japonicum from oxidative stress. rSjTPx-3 may represent a potential vaccine candidate and/or new drug target for patients with schistosomiasis.