Tryptanthrin is one of the well-known natural alkaloids with a broad spectrum of biological activities and can act as anti-inflammatory, anticancer, antibacterial, antifungal, antiviral, antitubercular, and other agents. Owing to its potent anticancer activity, tryptanthrin has been widely explored for the therapy of various cancers besides being effective against other diseases. Tryptanthrin with a pharmacological indoloquinazoline moiety can not only be modified by different functional groups to achieve various tryptanthrin derivatives, which may realize the improvement of anticancer activity, but also bind with different metal ions to obtain varied tryptanthrin metal complexes as potential anticancer agents, due to their higher anticancer activities in comparison with tryptanthrin (or its derivatives) and cisplatin. This review outlines the recent advances in the syntheses, structures, and anticancer activities of tryptanthrin derivatives and their metal complexes, trying to reveal their structure–activity relationships and to provide a helpful way for medicinal chemists in the development of new and effective tryptanthrin-based anticancer agents.