Abstract: P-glycoprotein (P-gp) is an important transmembrane ATP-binding cassette (ABC) drug efflux transporter expressed in various human tissues such as the intestines, liver, kidneys, and blood-brain barrier. It limits the intracellular concentration of xenobiotics by pumping them out of the cells, affecting drug pharmacokinetics and therapeutic effects. With its broad substrate specificity, it has the potential to remove a wide range of drugs from Chinese materia medica (CMM), including conventional medicines and active compounds. Increasing evidence has confirmed the superior therapeutic effectiveness of CMM in treating a wide range of diseases worldwide, as well as in conjunction with western drugs. As a result, herbal medicine-drug compounds have prompted widespread concern, with the majority of these interactions involving transporters such as P-gp. This review systematically summarizes the inhibition or induction of P-gp expression/function by active CMM compounds and the underlying regulatory mechanisms. It will aid in improving understanding of the synergistic or inhibiting effects associated with transporter P-gp as well as rational safety concerns for using CMM, particularly in combination with drugs.