<p>The versatility of N-acylhydrazone scaffolds in bioactive compounds stems from their ability to interact with diverse molecular targets, making them attractive candidates for drug development. A series of 13 quinoline hydrazones 3a–m was synthesized using both ultrasonic vibrations and conventional methods through the condensation reaction of quinoline hydrazide <b>2</b> with different arylaldehydes in an aqueous medium. Compared to conventional techniques, the ultrasonic method yielded significantly higher efficiencies and faster reaction times. The synthesized compounds were characterized using a combination of mass spectrometry, ¹H-NMR, and ¹³C-NMR techniques. Subsequently, their α-amylase inhibitory activity was evaluated in vitro, with acarbose as a standard reference. Four analogs demonstrated notable activity, characterized by IC₅₀ values ranging from 0.711 ± 0.020 to 1.105 ± 0.059 µM, relative to acarbose, which had an IC₅₀ of 0.399 ± 0.011 µM. Kinetic studies confirmed that they exhibited both non-competitive and uncompetitive inhibition modes. Molecular docking simulations were conducted to elucidate the interaction strength of the azomethine group and the different substitutions of the aryl moieties with the target enzyme. The docking scores correlated with the IC₅₀ values of the active compounds, with energy values ranging from − 8.6 to -7.0&#xa0;kcal/mol, and interaction patterns clearly demonstrated the structure-activity relationship. ADMET properties were simulated to assess their potential as drug candidates, indicating that they displayed favorable in silico ADMET profiles. This study describes the synthesis of novel quinoline hydrazones, four of which strongly inhibit α-amylase, demonstrating a favorable profile for drug candidates.</p>