Helianthus tuberosus L. (Jerusalem artichoke) tubers and aerial parts possess both nutritional and therapeutic properties. The Jerusalem artichoke has been utilized for various applications, including its use as a functional food source, a reservoir of bioactive compounds, and a raw material to produce biofuels. Moreover, the Jerusalem artichoke is a rich source of an indigestible polysaccharide called inulin, which serves as a prebiotic that improves gastrointestinal health. This plant has been used globally throughout history as a dietary supplement, for pain treatment, to reduce swelling, and to boost the immune system, as well as to treat skin wounds in folk medicine. It is an abundant source of bioactive compounds, such as phenolic acids, coumarins, and flavonoids, which are known to exert pharmacological activities, including antioxidant, antimicrobial, and anti-inflammatory properties. The literature on its potential as an antidiabetic, anticancer, anti-fungistatic, antiviral, and anti-obesity agent, among others, is scanty. This review aims to provide a comprehensive overview of Helianthus tuberosus L.’s traditional uses, nutritional properties, secondary bioactive compounds, and pharmacological properties to further explore its health benefits.