Combining two or more biologically active moieties in a single structure recently became one of the most proposed concepts that have been adopted in drug development process. Enhanced efficacy, limited side effects and declined drug resistance are the main features of molecular hybridization approach. Both imidazole and sulfonamide cores are valuable pharmacophores and precious structural motifs of highly anticipated medicinal interest that grabbed researchers’ attention in the last few years and could serve as lead candidates with prodigious antibacterial, antifungal, antiviral, anticancer, anti-inflammatory, anticholinesterase, antioxidant and antidiabetic significance. Imidazole tethered sulfonamides utilized a shotgun strategy through binding to different sites on receptor, hitting multiple targets and exhibiting synergized therapeutic potential, dual inhibitory activity against various diseases including drug-resistant forms with diminished adverse reactions. This comprehensive review focuses on the fruitful influence of connecting these two scaffolds in a single hybrid molecule and outlines the promising biological importance of some imidazole‒sulfonamide conjugates as multitarget‒directed ligands (MTDLs) in terms of structure‒activity relationships.