We have recently developed pollen grains (PGs) as a unique method to deliver vaccines orally. Extensive chemical processing ensures allergen-free pollen microcapsules that can be loaded with vaccine antigens. Successful oral vaccine delivery has been previously demonstrated by us in a mouse model. However, the underlying mechanisms that help the processed PGs to achieve this goal were not fully understood. In this study, we wanted to understand the effects of chemically processed ragweed pollen (Ambrosia elatior) on the innate immune system. Intestinal epithelial cells, macrophages, and dendritic cells all bridge the innate and adaptive immunity. This study has shown that in response to ragweed pollen all these cells release inflammatory cytokines and chemokines. Scanning electron microscopy imaging revealed that macrophages can engulf ragweed pollen. In addition, in the presence of ragweed, mouse dendritic cells upregulated their activation markers, that is, CD40, CD80, CD86, and MHC class II molecules. Ragweed pollens did not cause significant cell membrane damage as compared to similarly sized poly (lactic-co-glycolic acid) particles. Moreover, ragweed did not affect the integrity of the intestinal epithelial cells. Ragweed pollens were also found in the subepithelial region of the small intestine 24 h after pollens were gavaged to mice. Our current findings lead to the conclusion that besides transporting the vaccine cargo, ragweed pollen shells have additional immunomodulatory properties that help the orally delivered antigen to effectively induce an immune response.