Background: Calotropis gigantea (CG) is a shrubby plant which is traditionally used for the treatment of diseases affecting the nervous system, digestive system, and skin. Several bioactive compounds from CG are isolated and investigated for their pharmacological properties. Methods: A systematic analysis of PubMed, Google Scholar, and PubChem database was performed, and the pharmacognosy and pharmacological properties of CG compounds were correlated. Results: Major phytochemicals such as those of the cardenolide, uscharin, and calotropin family were dominant in the CG plant. Phytochemicals found in the leaves, root, and latex of CG plant showed selective cytotoxicity, proapoptotic effects, and cell cycle arrest potential by modulating hypoxia-inducible factor 1 α, inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-β), Notch, and Wnt signaling. Conclusion: The selective cytotoxicity against neuronal tumors, together with their neurogenesis/synaptogenesis potential and drug candidate like features merit the development of CG compounds as therapeutics for neuronal tumors.