Sulfonamide has medicinal properties and molecular mobility that serve as key synthetic bioactive molecules in pharmaceutical science. Since the discovery of Prontosil in the early 1900s, sulfonamides have been widely studied as antibacterial agents targeting folate biosynthesis. Recent modifications to structures using heterocyclic rings, electron-withdrawing substituents, and hybrid pharmacophores have improved their antibacterial, anticancer, anti-inflammatory, antiviral, and enzyme inhibitory activities. This review covers current breakthroughs in sulfonamide derivative production, biological activity, resistance mechanisms, and therapeutics. Microwave-assisted and green synthesis methods, molecular docking, ADMET prediction, and targeted therapeutics are prioritized. Through suppression of carbonic anhydrases, cyclooxygenases, histone deacetylases, and dihydropteroate synthases, sulfonamide derivatives were effective against multidrug-resistant infections and various human cancer cell lines. Many derivatives have good receptor-binding interactions and pharmacokinetics, according to computational studies. However, bacterial resistance, toxicity, and hypersensitivity responses remain clinical issues, and nanotechnology, AI-assisted drug discovery, and multitarget therapy design which that increase sulfonamide-based treatment selectivity and efficacy.