The present review article includes recent advances in the synthesis of structurally and functionally diversified quinoxalines‐drug‐like small molecules with molecular complexity. We have extended our efforts to include the research work concerning the isocyanide‐based multicomponent reactions. The synthetic methods included in the present review article will provide an access for a diverse range of natural product mimetic scaffolds with the use of isocyanide‐.based combinatorial synthesis. These isocyanide based reactions will be significant for the synthesis of complex bioactive natural products and potential synthetic pharmaceuticals. The present review will contribute considerably to the organic syntheses and particularly drug discovery research including pharmaceutical and medicinal chemistry. Academically, the present review article will be interesting for the researchers engaged in design and development of isocyanide‐based organic transformations. Moreover, we hope that the isocyanide‐based multicomponent reactions will find major applications in industrially significant organic transformations and to develop new synthetic routes to facilitate the incorporation of heterocyclic substructures into pharmaceutically active molecules.