The species of Cleome genus are taxonomically included in the family of Cleomaceae and in the order of Brassicales, representing flowering plants with a long history of use in traditional medicine. Phytochemical screening experiments revealed that Cleome species contain a wide range of beneficial bioactive compounds, including alkaloids, essential oils, fatty acids, flavonoids, terpenes, sterols, and anthocyanins, indicating a therapeutic potential. Furthermore, due to the presence of these phytocompounds, there are various plant species in this genus that have demonstrated a wide range of genotypic, chemo typic, and biological activity in several ecological settings around the world. The potential biological actions and pharmacological effects, such as analgesic, anti-inflammatory, antipyretic, anti-diabetic, antidepressant, antibacterial, anti-arthritic, anticancer, and hepatoprotective are closely related to the active substances contained in various parts of the plants. By centralizing medical data provided by the scientific literature, we offer in the present work a comprehensive perspective on a wide range of bioactive compounds identified from diverse Cleome species, emphasizing the correlation of natural active substances with potential pharmacological activities that can contribute to the improvement of therapeutic management for a range of pathologies. In addition, this review suggests future research perspectives to improve the use of phytochemicals contained in the species of Cleome genus, both in terms of increasing therapeutic efficacy and safety profiles, but also in terms of identifying a possible new pharmacological effect.