Evodiamine (EVO) is a natural quinolone alkaloid firstly isolated from the fruit of Evodia ru-taecarpa, which is one of the most frequently used traditional Chinese herb for treating a variety of ail-ments, including headaches, abdominal pain, vomiting, diarrhea, amenorrhea difficult menstruation, postpartum hemorrhage, and other diseases. Latest pharmacological studies showed that EVO possesses a broad spectrum of pharmacological activities through different mechanisms. However, its moderate activities and poor physicochemical properties have hampered its clinical application. In this regard, the modification of EVO aiming at seeking derivatives with more potency and better physicochemical properties has been extensively emerging. These derivatives exhibit diverse biological activities, including antitumor, anti-Alzheimer's disease, anti-pulmonary hypertension, anti-fungi, and thermogenic activities via a variety of mechanisms. Moreover, they are described to act as single, dual, or multiple inhibitors or agonists of many proteins, such as topoisomerase I, topoisomerase II, tubulin, histone deacetylase, sirtuins, butyrylcholinesterase, phosphodiesterase 5, and transient receptor potential vanilloid 1. Howev-er, hitherto, there is no comprehensive review to systematically summarize the derivatives of EVO. Considering this perspective, this paper aims to provide a comprehensive description of them by focusing on their diverse biological activities. For each biological activity, the mechanisms and the main structure-activity relationships (SARs) will be presented in cases where adequate information is available. Finally, future directions of this class of compounds will be discussed. This review will be helpful in understand-ing and encouraging further exploration of EVO. © 2022 Bentham Science Publishers.