Background: Plants have been used as ethnomedicines for centuries in various communities to treat maladies. Poor dietary choices and lifestyle practices have immensely increased the disease burden, which has diverted the attention of scientists to explore medicinal plants for the development of nutraceuticals and functional foods. Scope and approach: This review discusses in detail the applications of Citrullus colocynthis, an herbaceous medicinal plant commonly found in sandy, arid, and semi-arid regions, especially in Asia, Africa, and the Mediterranean region. Key findings and conclusion: Bioactive compounds, especially cucurbitacin, polyphenols, flavonoids, and phytosterols, attenuate reactive oxygen and nitrogen species and help reduce pro-inflammatory markers (cyclooxygenase and lipoxygenase), which are effective in the management of diabetes, liver cirrhosis, neuropathy, arthritis, cancer, and vascular disorders. It is worth mentioning that C. colocynthis is safe to use with minimal side effects, such as gastric irritation and hepatic toxicity, if consumed in upper tolerable limits (similar to 400 mg/kg). The nutraceutical and pharmaceutical industries can develop herbal medicines from this plant to improve human health. Although much research has been conducted to validate the therapeutic potential of C. colocynthis, clinical evidence is lacking, and further studies in this domain are required to transform traditional knowledge fully and claims into practical implications.