N-Heterocyclic scaffolds have generated significant interest among medicinal chemists. Among these potential heterocyclic drugs, benzimidazole and imidazopyridine scaffolds are the most prevalent. Over the past few decades, it has gained immense attention. Both are important classes of molecules owing to their wide spectrum of biological activities and clinical applications. Both are used in fashion design and the development of novel synthetic analogs for various therapeutic disorders. A wide variety of derivatives have been developed as potential anticancer, antimicrobial, antiviral, and anti-inflammatory agents in addition to other chemotherapeutic agents. The benzimidazole core is found in a natural system, displaying a wide range of pharmaceutical properties, and has gained significant attention in medicinal chemistry, as reported in several full articles and communications. Imidazopyridines are widely distributed in many pharmacologically important compounds, as shown by their frequent occurrence in a large number of marketed drug formulations and drug candidates, as well as in other fields such as material and organometallic chemistry. These scaffolds have been structurally characterized as ligands that can bind to different receptor sites for the discovery of various emerging drugs. They act as key pharmacophore motifs for the identification and optimization of lead structures to increase the medicinal chemistry toolbox. This review outlines the synthesis and medicinal significance of benzimidazoles and imidazopyridines for their development as lead molecules with improved therapeutic efficiency. Here, we cover the various designs used to obtain both heterocycles to establish a relationship between their combination and biological activities.