Objective To evaluate effects on the innate immune system after exposure to, a consumable low-molecular weight fraction (CLMWF) of immunoglobulin-depleted bovine colostrum whey. Methodology Cell-based immune assays were performed in vitro, and host resistance towards bacterial and viral infection was evaluated in two mouse studies. Results In vitro data showed a multimodal effect, as CLMWF treatment resulted in a rapid increase in phagocytosis. CLMWF increased chemotaxis of polymorphonuclear cells towards the bacterial peptide f-MLP. CLMWF treatment of natural killer cells increased expression of the CD69 activation marker. Mononuclear phagocytes showed decreased numbers of CD14bright and increased number of CD14dim cells. The remaining CD14bright cells showed reduced expression of CD80 and CD86, whereas CD14dim cells showed increased expression of CD80 and CD86, suggesting dendritic cell maturation. Mouse models were applied to evaluate the immune-modulating capacity of CLMWF when consumed acutely during bacterial (Streptococcus) and viral (Influenza) infections in vivo. Reduced bacterial and viral loads were observed in lungs within 24 h. Viral load was also reduced when CLMWF was introduced intranasally. Conclusion The data suggest that the support of antimicrobial immune defense mechanisms and maturation of antigen-presenting cells in vitro translates to protection in vivo when product is introduced across mucosal membranes.