Milk has long been associated with good health and is one of the most consumed beverages throughout the world. Exosomes are 30-150 nm membranous vesicles of endocytic origin that are released by all cell types and are also detected in bodily fluids including milk. These extracellular vesicles play significant role in intracellular communication and immune modulation via transferring functionally active cargo (miRNA, mRNA, DNA and proteins). Whether these milk-derived exosomes can serve as cross-species messengers and have a biological effect on the recipient cells in the host has been poorly understood. In this study, using mouse models, we show that orally administered milk-derived exosomes can survive the harsh intestinal environment. Using in vivo tracking methods, the bio distribution of the milk-derived exosomes was studied until 96 h after oral administration. After 48 h, the milk-derived exosomes reached multiple organs including liver and spleen in the mice. A follow up quantitative proteomics analysis was performed to characterize the milk-derived exosomes to understand their role in general physiology on oral ingestion. The remarkable stability of milk-derived exosomes was compared to colorectal cancer cell-derived exosomes. We also investigated the therapeutic potential of milk-derived exosomes by investigating the effect on oral intake by mice implanted with human colon cancer. This study thus provides new insights on the significance of milk-derived exosomes in context to mammalian physiology as well as prompt their use as drug delivery vehicles in therapeutic interventions.