Tissue damage in Schistosoma mansoni infection results from a granulomatous, T cell-mediated response to parasite eggs, leading to liver fibrosis and portal hypertension. This immune response, initially Th1-dominated, progressively shifts toward a Th2 profile, contributing to hepatic stellate cell (HSC) activation and fibrosis. However, the precise regulatory mechanisms remain unclear. In this study, we analyzed T cell responses to soluble egg antigens (SEA) in 121 T cell clones (Tcc) from S. mansoni-infected patients. All clones produced high levels of IL-13 upon anti-CD3 stimulation; a minority secreted IFN-γ (n = 33) or IL-10 (n = 38). Notably, 51 clones co-produced IL-22 and IL-13. To investigate IL-22's role, we examined IL-22 receptor (IL-22R) expression on human M0 and M2 macrophages. Both subsets expressed IL-22R, and its engagement triggered phosphorylation of p38, STAT3, and STAT5. IL-22 also downregulated IL-13-induced M2 markers (CD163, CD200R). Furthermore, IL-22 treatment of HSCs inhibited IL-13-driven collagen I/III production and cell proliferation. These results suggest that IL-22-producing T cells modulate Th2 macrophage polarization and directly suppress fibrogenesis in HSCs. IL-22 may thus act as a regulatory cytokine counteracting liver fibrosis during schistosomiasis.