Chalcones (1,3-diaryl-2-propen-1-ones) represent a versatile class of bioactive molecules widely explored for antimicrobial drug development. Structural hybridization of chalcones with nitrogen-containing heterocycles has attracted significant attention due to the synergistic enhancement of biological activity achieved by combining multiple pharmacophores within a single molecular framework. This review provides a comprehensive overview of recent developments in nitrogen heterocycle-linked chalcone hybrids, with particular emphasis on indole-, triazole-, pyrazole-, and quinoline-based derivatives. Synthetic methodologies including Claisen–Schmidt condensation, Cu(I)-catalyzed azide–alkyne cycloaddition, Vilsmeier–Haack formylation, and heterocyclic cyclization strategies are discussed in detail. Reported antimicrobial investigations demonstrate that several hybrids exhibit potent activity against Gram-positive and Gram-negative bacteria as well as pathogenic fungi, with minimum inhibitory concentrations approaching those of established therapeutic agents. Structure–activity relationship analyses highlight the crucial influence of electron-withdrawing substituents, heterocyclic nitrogen positioning, and molecular planarity on target affinity. Furthermore, molecular docking studies support multi-target interactions, particularly against microbial DNA gyrase and lanosterol 14α-demethylase, rationalizing the observed bioactivity. Collectively, nitrogen heterocycle-linked chalcones constitute promising lead scaffolds for the development of next-generation antimicrobial agents and merit further pharmacological and clinical exploration.