In the present study, a hydrazone-linked thiazole derivative, (E)-4-(4-chlorophenyl)-2-(2-(1-(2,4-difluorophenyl)ethylidene)hydrazineyl)thiazole (4), was successfully synthesized via a one-pot multicomponent reaction involving 1-(2,4-difluorophenyl)ethan-1-one, thiosemicarbazide, and 2-bromo-1-(4-chlorophenyl)ethan-1-one in ethanol using glacial acetic acid as a catalyst. The structure of the synthesized compound was confirmed through detailed spectroscopic analysis using ¹H NMR and ¹³C NMR techniques. The pharmacokinetic properties of the compound were evaluated using in-silico ADME analysis via SwissADME, indicating favourable drug-like characteristics, including high gastrointestinal absorption, moderate solubility, acceptable polarity and compliance with major drug-likeness rules with minimal violations. The compound exhibited relatively high lipophilicity and was predicted to be non-permeable to the blood–brain barrier, suggesting selective peripheral activity. Molecular docking studies against Cytochrome P450 14α-sterol demethylase (CYP51), a key enzyme involved in sterol biosynthesis in Mycobacterium tuberculosis, demonstrated a strong binding affinity (−9.9 kcal/mol). The ligand exhibited a stable binding conformation within the active site, stabilized by a combination of hydrogen bonding, halogen interactions, π–π stacking, π–sulfur interactions, and extensive hydrophobic contacts with key amino acid residues and the heme group. The presence of fluorine and chlorophenyl substituents significantly contributed to enhanced binding interactions and stability. The combined synthetic, spectral, pharmacokinetic, and molecular docking results suggest that the synthesized thiazole-based hydrazone derivative represents a promising scaffold for further development as a potential antitubercular agent, warranting additional biological evaluation and optimization studies.