It has been reported previously that oral administration of lactoferrin (LF) provides some host-protective effects against infections, cancers, and inflammations. In this review, we focus on the effect of oral LF on various infectious diseases and discuss the mechanism as elucidated in animal models. In the case of infections occurring at sites other than the digestive canal, it is unclear whether oral LF is absorbed from the intestine and exerts its protective effect at the site of infection. In preterm human infants, neonatal pigs, and rats with colitis, it was reported that LF is detectable in various body fluids after oral administration. We could not detect the transport of oral bovine LF into the blood of adult rats without gastrointestinal illness using several techniques, suggesting that there is an extremely low level of transport of LF, if any. Orally administered LF may act at the oro-gastro-intestinal mucosa and aid the defense system against infections through a network of mucosal immunity and systemic immunity. Indeed, it is reported that oral LF increases the number of cells in the leukocyte subset and cytokine (IFN-gamma and IL-18) production in the intestinal mucosa of mice. Regarding systemic immunity, we have observed an increase of leukocyte number, cytokine (IFN-gamma, TNF-alpha, IL-12, and IL-18) production, and effector activity of macrophages in response to LF administration in several animal models. These enhanced immune responses may contribute to eradication of the pathogen, resolution of the symptoms, and maintenance of the homeostasis during infectious diseases.