Hypericum L. genus plants are distributed worldwide, with numerous species identified throughout all continents, except Antarctica. These plant species are currently used in various systems of traditional medicine to treat mild depression, wounds and burns, diarrhea, pain, fevers, and their secondary metabolites previously shown, and the in vitro and/or in vivo cytotoxic, antimicrobial, anti-inflammatory, antioxidant, antihyperglycemic, and hepatoprotective activities, as well as the acetylcholinesterase and monoamine oxidase inhibitory activities. We conducted a systematic bibliographic search according to the Cochrane Collaboration guidelines to answer the question: “What is known about plants of Hypericum genus as a source of natural products with potential clinical biological activity?” We documented 414 different natural products with confirmed in vitro/in vivo biological activities, and 58 different Hypericum plant species as sources for these natural products. Phloroglucinols, acylphloroglucinols, xanthones, and benzophenones were the main chemical classes identified. The selective cytotoxicity against tumor cells, cell protection, anti-inflammatory, antimicrobial, antidepressant, anti-Alzheimer’s, and adipogenesis-inhibition biological activities are described. Acylphloroglucinols were the most frequent compounds with anticancer and cell-protection mechanisms. To date, no work has been published with a full descriptive list directly relating secondary metabolites to their species of origin, plant parts used, extraction methodologies, mechanisms of action, and biological activities.