This study reports design and synthesis of novel highly functionalized furan analogues bearing imidazole–thiazole hybrids with potential antimicrobial activity. The synthesized compounds were prepared and characterized using spectroscopic tools and elemental analyses. The antimicrobial activity of all the synthesized compounds was evaluated against a panel of bacterial strains vs ciprofloxacin as the positive control. The results revealed a highly structure‐ and strain‐dependent profile. However, compound 9b emerged as the most potent activity. To enhance the physicochemical and biological performance, selected bioactive compounds ( 6b , 8a,c ; 9b,c ; and 11a ) were formulated into nanoparticles and characterized, performing acceptable sizes, stability and distribution profiles, while 9b exhibited the favorable parameters. The antimicrobial evaluation for the 6‐nanoformulations was assessed and compared with their parent compounds. Nano‐compounds 9b > 9c > 8c demonstrated the most potent activity, and lowest MIC values, comparable and even superior to ciprofloxacin in several cases. Molecular docking studies and molecular dynamic simulations were conducted to 9b to get a detailed view including its proposed binding behavior, interaction patterns, conformational rearrangements, and stability within the DNA gyrase B active site compared with that of novobiocin. The findings validate 9b as the most promising candidate for further development as a DNA gyrase B inhibitor.