N-heterocyclic scaffolds represent a privileged architecture in the process of drug design and development. It has widespread occurrence in synthetic and natural products, either those that are established or progressing as potent drug candidates. Additionally, numerous novelN-heterocyclic analogues with remarkable physiological significance and extended pharmaceutical applications are escalating progressively. Hence, the classical synthetic protocols need to be improvised according to modern requirements for efficient and eco-friendly approaches. Numerous methodologies and technologies emerged to address the green and sustainable production of various pharmaceutically and medicinally importantN-heterocyclic compounds in last few years. In this context, the current review unveils greener alternatives for direct access to categorically differentiatedN-heterocyclic derivatives and its application in the establishment of biologically active potent molecules for drug design. The green and sustainable methods accentuated in this review includes microwave-assisted reactions, solvent-free approaches, heterogeneous catalysis, ultrasound reactions, and biocatalysis.