A novel series of acyl hydrazone derivatives was synthesized by condensing acyl hydrazide of 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid with various substituted aldehydes under reflux, in the presence of a catalytic amount of mineral acid. The reaction progress and purity of the synthesized compounds were monitored by TLC, and their melting points were recorded. Structural characterization was carried out using HRMS, FT-IR, and 1H and 13C NMR, confirming the successful formation of the target compounds. The synthesized compounds were further evaluated for their ADME profiles to assess drug-likeness and pharmacokinetic behavior. Antimicrobial activities were screened against selected bacterial strains, including gram-positive (Staphylococcus aureus, Bacillus cereus) and gram-negative (Salmonella typhimurium, Escherichia coli) organisms, using Tetracycline as a reference standard. The results demonstrated that several compounds exhibited notable antimicrobial properties. Among the tested derivatives, HAS-01 and HAS-03 showed the most promising activity, with significant inhibition against both gram-positive and gram-negative bacteria. These compounds also displayed favorable ADME characteristics, suggesting their potential as lead candidates for further development. The study highlights the importance of the thiazole-based acyl hydrazone scaffold in designing new antimicrobial agents and provides a strong foundation for further optimization and structure–activity relationship studies.