Piperine, a crystalline alkaloid compound isolated from Piper nigrum, piper longum, and other types of piper, has had many fabulous pharmacological advantages for preventing and treating some specific diseases, such as analgesic, anti-inflammatory, hepatoprotective, antimetastatic, antithyroid, immunomodulatory, antitumor, rheumatoid arthritis, osteoarthritis, Alzheimer's, and improving the bioavailability of other drugs. However, its potential for clinical use through oral usage is hindered by water solubility and poor bioavailability. The low level of oral bioavailability is caused by low solubility in water and is photosensitive, susceptible to isomerization by UV light, which causes piperine concentration to decrease. Many different formulation approaches have been applied to improve the poor oral bioavailability of piperine. There have been oral formulation strategies that have been successfully implemented in increasing the solubility and bioavailability of piperine within the body, such as the formulation of nanoparticles, nanosuspensions, salt formation, liposomes, complexation using polymers, micro/nano-emulsions, and solid dispersions. This review presents a summary of piperine biopharmaceuticals, new formulation design approaches to improve oral bioavailability of piperine, and several techniques and methods for conducting selective and sensitive analysis of piperine in biological fluids.