Impairment of the intestinal mucosal immunity significantly increases the risk of acute and chronic diseases. Immunoglobulin A (IgA) plays a major role in humoral mucosal immunity to provide protection against pathogens and toxins in the gut. Here, we investigated the role of endogenous galectin-9, a tandem repeat-type β-galactoside–binding protein, in intestinal mucosal immunity. By mucosal immunization of Lgals9^−/−and littermate control mice, it was found that lack of galectin-9 impaired mucosal antigen-specific IgA response in the gut. Moreover, Lgals9^−/− mice were more susceptible to developing watery diarrhea and more prone to death in response to high-dose cholera toxin. The results indicate the importance of galectin-9 in modulating intestinal adaptive immunity. Furthermore, bone marrow chimera mice were established and galectin-9 in hematopoietic cells was found to be critical for adaptive IgA response. In addition, immunized Lgals9^−/− mice exhibited lower expression of Il17 and fewer T_H17 cells in the lamina propria, implying that the T_H17–IgA axis is involved in this mechanism. Taken together, these findings suggest that galectin-9 plays a role in mucosal adaptive immunity through the T_H17–IgA axis. By manipulating the expression or activity of galectin-9, intestinal mucosal immune response can be altered, and may benefit the development of mucosal vaccination.