BACKGROUND: Antibiotic resistance is a growing global threat due to antibiotic overuse and limited treatment options. Multidrug-resistant bacteria, like Staphylococcus aureus and Escherichia coli, increase infection complexity and mortality. This study explores nanocomposite films of ZIF-8 nanoparticles and Doxycycline (Dox) to enhance antibacterial efficacy. In this study, nanocomposite films composed of chitosan (CS) and polyethylene glycol (PEG), incorporating zeolitic imidazolate framework-8 (ZIF-8) nanoparticles and DOX, were developed. These films were characterized by their morphological, mechanical, antibacterial, and drug-release properties. Antibacterial efficacy was evaluated using disk diffusion, broth microdilution, and checkerboard assay methods to determine MICs and potential synergistic effects. RESULTS: The nanocomposite films demonstrated flexibility, semi-transparency, and a yellowish-brown hue, with films containing ZIF-8 nanoparticles being thicker (79 ± 0.2 μm) than those without (54 ± 0.5 μm). The tensile strength was enhanced with the incorporation of ZIF-8, peaking at 53.12 MPa for the CS-PEG-G-10% DOX-4% ZIF-8 film. XRD analysis confirmed the crystallinity of the ZIF-8 and DOX, with distinct peaks observed for each material. The drug release studies revealed an initial burst followed by sustained release, with higher release rates in acidic environments compared to neutral and alkaline media. The CS-PEG-G-10% DOX-4% ZIF-8 nanocomposite film demonstrated significantly higher antibacterial activity, achieving the lowest MIC values, particularly against S. aureus (22.5 mm inhibition zone) compared to E. coli (14 mm inhibition zone). Additionally, a notable synergistic effect was observed between CS-PEG-G-10% DOX and CS-PEG-G-10% DOX, with FICI values below 0.5. CONCLUSIONS: The CS-PEG-G-10% DOX-4% ZIF-8 nanocomposite exhibits enhanced antibacterial efficacy and optimal properties, positioning it as a strong candidate for developing effective treatments against multidrug-resistant pathogens.