Supplementation with mushroom-derived active hexose correlated compound (AHCC) modulates immunity and increases survival in response to a broad spectrum of acute infections, including influenza virus infection. However, dose-response data are nonexistent. Therefore, the aims of this study were to evaluate AHCC supplementation at various doses and determine the effects of low-dose supplementation on the immune response in a mouse model of influenza virus infection. We hypothesized that AHCC supplementation would influence the immune response to influenza infection in a dose-dependent manner. Male C57BL/6 mice were supplemented with AHCC at daily doses of 0.05, 0.1, 0.5, and 1 g/kg and infected intranasally with influenza A virus (H1N1, PR8). Supplemented mice demonstrated a dose-dependent increase in survival and reduction in the loss of body weight. To further evaluate the effects of low-dose AHCC supplementation on the immune response to influenza infection, mice were supplemented with 0.1 g/kg per day and infected with a sublethal dose of influenza virus. Supplemented mice exhibited enhanced virus clearance and decreased weight loss compared to controls. Low-dose supplementation did not influence total natural killer (NK) cell cytotoxicity, although lytic efficiency was increased in the spleens of AHCC-supplemented mice, indicating enhanced NK cell function per cell. In conclusion, these data suggest that the effects of AHCC on the immune response to influenza infection are dose dependent and that low-dose AHCC supplementation improves the response to influenza infection despite no effect on total NK cell cytotoxicity.