The genus Helichrysum Mill comprises hundreds of species that are mostly flowering perennial shrubs. Some of these plants that belong to the Helichrysum species are used in traditional medicine to treat cough, back pain, diabetes, asthma, digestive problems, menstrual pain, chest pain, kidney disorders, skin disorders, wounds, open sores, among other conditions, but, only a few scientific studies are reported in the literature with sufficient information that validates the acclaimed folkloric benefits of these plants. This review, therefore, provides a comprehensive update of the available information on the cytotoxicity, genotoxicity, anti-proliferative, anti-bacterial, anti-fungal, anti-viral, anti-HIV, anti-malarial, anti-ulcerogenic, anti-tyrosinase, anti-inflammatory, and anti-oxidant activities of selected Helichrysum species of interest: H. petiolare, H. cymocum, H. foetidum, and H. pandurifolium Schrank, using scientific databases as well as electronic and print sources. The ethnobotanical and morphological characteristics as well as the phytochemical composition and biological activities of these plants are elucidated. The scientific rationale for their current use is discussed based on the evidence in the literature. This review highlights the putative use of the Helichrysum species as a reliable source of bioactive compounds for the production of standard commercial drugs to treat many ailments, including those reported in folkloric uses. Further research on the many plants in the genus Helichrysum is recommended to explore their economic importance both as edible crops and medicinal botanicals.