Objective To investigate the impact of E-cadherin (E-cad) overexpression on hepatic epithelial-mesenchymal transition (EMT) and liver fibrosis induced by Schistosoma japonicum infection. Methods A total of 16 mice were randomly divided into the E-cad group and the control group, and were injected with 2 × 10¹¹ vector genomes of E-cad plasmid or empty plasmid packaged with adeno-associated virus 8 via the tail vein. All mice were infected with S. japonicum cercariae [(20 ± 1) per mouse] via the abdomen 3 weeks post-injection, and liver tissues were collected 6 weeks post-infection. Total RNA was extracted from liver tissues, and the relative transcription levels of target genes were detected with a real-time quantitative PCR (qPCR) assay. Total protein was extracted from liver tissues, and the relative expression of target proteins was detected using Western blotting. Paraffin-embedded liver sections were stained with hematoxylin and eosin (HE) and Masson’s trichrome stains to assess the area of single-egg granulomas and collagen fibers. All statistical analyses were performed using the software GraphPad Prism 9, and differences of means between groups were assessed using t-test. Results The relative mRNA transcription levels of E-cad were 1.15 ± 0.07 and 7.19 ± 2.43 in mouse liver tissues in the control and E-cad group (t = 4.30, P < 0.05), and the relative protein expression of E-cad were 1.03 ± 0.16 and 1.42 ± 0.22 in the control and E-cad group (t = 3.62, P < 0.01), indicating successful modeling of hepatic E-cad overexpression in mice. qPCR assay quantified lower relative mRNA transcription of vimentin (Vim) [(0.60 ± 0.17) vs. (1.37 ± 0.33); t = 3.60, P < 0.05], α-smooth muscle actin (α-SMA) [(0.62 ± 0.19) vs. (1.43 ± 0.35); t = 3.48, P < 0.05], collagenⅠ (Col-1) [(0.31 ± 0.17) vs. (1.78 ± 0.84); t = 3.74, P < 0.05] and collagenⅢ (Col-3) [(0.30 ± 0.13) vs. (1.78 ± 0.45); t = 5.52, P < 0.01] in mouse liver tissues in the E-cad group than in the control group, and Western blotting determined lower relative expression of Vim [(0.22 ± 0.13) vs. (0.71 ± 0.13); t = 4.39, P < 0.01], N-cadherin (N-cad) [(0.37 ± 0.14) vs. (0.65 ± 0.08); t = 2.75, P < 0.05], α-SMA [(0.29 ± 0.19) vs. (0.81 ± 0.13); t = 3.91, P < 0.01], Col-1 [(0.23 ± 0.06) vs. (0.43 ± 0.08); t = 3.99, P < 0.01], Col-3 [(0.17 ± 0.02) vs. (0.50 ± 0.16); t = 3.47, P < 0.05], transforming growth factor-β1 (TGF-β1) [(0.32 ± 0.13) vs. (0.68 ± 0.07); t = 3.92, P < 0.01], Smad2 [(0.57 ± 0.14) vs. (0.87 ± 0.04); t = 2.95, P < 0.05] and Smad3 [(0.54 ± 0.10) vs. (0.82 ± 0.06); t = 4.61, P < 0.05] in mouse liver tissues in the E-cad group than in the control group. HE staining showed that the area of single-egg liver granulomas were [(34.10 ± 6.94) × 10⁴] and [(12.76 ± 3.16) × 10⁴] μm² in the control and E-cad groups (t = 7.41, P < 0.01), and Masson staining showed that the areas of collagen fibers with single-egg liver granulomas were [(8.50 ± 2.36) × 10⁴] and [(3.65 ± 0.90) × 10⁴] μm² in the control and E-cad groups (t = 5.01, P < 0.01), respectively. Conclusion Hepatic E-cad overexpression alleviates EMT and liver fibrosis induced by S. japonicum infection in mice, potentially through inhibition of the TGF-β1/Smad signaling pathway.