The immunomodulatory nature of lactoferrin (LF) derives from its ability to bridge innate and adaptive immunity in obtaining physiological equilibrium. LF is an attractive molecule for treatment of diseases that compromise immune homeostasis. Oral delivery is a preferable method for LF administration; however, its bioavailability is affected by protein degradation and absorption. The aim of this study was to evaluate the systemic effects of oral and intravenous (IV) administered recombinant human LF (rhLF) on blood cell transcriptome profiling. Rats were administered with a single dose of rhLF by gavage or IV. The transcriptome profiles from control and rhLF-treated rats after 3h, 6h and 24h were analyzed by Clariom D microarray. The results showed differentially expressed genes in response to IV as well as oral administered rhLF including coding and noncoding RNAs. Moreover, a comparison of the differentially expressed genes between oral and IV after 6h revealed that a majority (72.8%) of altered genes in response to oral rhLF administration was common with IV treatment. The pathway profiles showed similarities in up-regulation of specific genes involved in oxidative stress and inflammatory responses for both routes of treatments. These findings provide evidence of the systemic signal transduction effects of orally administered rhLF.