Citrullus colocynthis (L.) Schrad is an ancient plant that grows in desert areas worldwide. Its fruit is known for its medicinal uses and potential applications in the pharmaceutical and nutraceutical industries. This narrative review aims to evaluate the published information on the ethnobotanical knowledge, phytochemistry, ethnopharmacology, nutraceutical potential, and toxicological studies of C. colocynthis, highlighting gaps and potential areas for future research. The present review extensively compiles, reviews, and analyzes the best available evidence from PubMed, Scopus (Embase), Web of Science (Web of Knowledge), Cochrane Library, Google Scholar, and other sources. Scientific literature shows that C. colocynthis contains bioactive compounds such as cucurbitacin, polyphenols, flavonoids, and other potent molecules that contribute to its antidiabetic, anticancer, antioxidant, antimicrobial, and anti-inflammatory properties. However, its potential therapeutic applications for digestive and respiratory systems, and cardiovascular disorders require further exploration. The present review reveals that the plant has significant potential for pharmaceutical and nutraceutical applications, with indications of synergistic effects and combinations that neutralize side effects.