Lactobacillus fermentum UCO-979C (Lf979C) beneficially modulates the cytokine response of gastric epithelial cells and macrophages after Helicobacter pylori infection in vitro. Nevertheless, no in vivo studies were performed with this strain to confirm its beneficial immunomodulatory effects. This work evaluated whether Lf979C improves protection against H. pylori infection in mice by modulating the innate immune response. In addition, we evaluated whether its exopolysaccharide (EPS) was involved in its beneficial effects. Lf979C significantly reduced TNF-α, IL-8, and MCP-1 and augmented IFN-γ and IL-10 in the gastric mucosa of H. pylori-infected mice. The differential cytokine profile induced by Lf979C in H. pylori-infected mice correlated with an improved reduction in the pathogen gastric colonization and protection against inflammatory damage. The purified EPS of Lf979C reduced IL-8 and enhanced IL-10 levels in the gastric mucosa of infected mice, while no effect was observed for IFN-γ. This work demonstrates for the first time the in vivo ability of Lf979C to increase resistance against H. pylori infection by modulating the gastric innate immune response. In addition, we advanced knowledge of the mechanisms involved in the beneficial effects of Lf979C by demonstrating that its EPS is partially responsible for its immunomodulatory effect.