Considering the very important medicinal and biological properties of heterocycles including isatin skeleton, synthesis of isatin-containing compounds has attracted the attention of medicinal and organic chemists, especially researchers involved in the synthesis of heterocycles. The present review focuses on the recent investigation in the synthesis of heterocycles with isatin moiety using isatin derivatives as reaction reactants via multi-component for the period of 2014–2024. The reports were classified according to the conditions of the reactions, which distinguishes this review from similar studies. In some reports, green chemistry has been used, such as the use of green solvent, green and reusable catalyst, solvent-free conditions, microwave irradiations and ultrasonic irradiations. Most reviews of isatin published so far have focused only on spirooxindoles, but this review not only addresses the condition for the synthesis of spirooxindoles, but also the synthesis of other isatin-contaning heterocycles such as pyrroloquinolines, imidazole-indoles and pyrazoloquinoline. The main objective of this review is to present an overview of the latest methodologies involving isatin in the multicomponent synthesis of heterocyclic compounds, specifically for organic and medicinal chemists.