Oral drug delivery is a promising approach for the treatment of various gastrointestinal (GI) diseases but poses significant challenges to target non-GI diseases. The intestinal barrier forms a significant anatomical challenge to reach the target diseased site, along with various physiological challenges such as stability in the GI tract. These challenges lead to development of various targeted nanoparticles and strategies to cross intestinal barrier and protect them from harsh conditions in the GI tract, improving absorption into the circulatory system, improving bioavailability, and ensuring a regulated release. Targeting ligands such as chitosan, Butyrate (BU), and yeast capsule (YC) shows effective permeability across the intestinal epithelium. After crossing the intestinal epithelium, these targeted strategies can effectively treat various non-GI diseases such as atherosclerosis, cancers, neurodegenerative diseases, fibrosis, and post-traumatic osteoarthritis. However, various challenges including stability and low bioavailability still persist, which can reduce the efficacy of these therapeutics and should be considered in designing potential therapies for non-GI diseases in the near future.