In the era of antibiotic resistance, antimicrobial polymers represent state of the art innovation evolved to fight biofilm-associated infections. In the present study, novel self-disinfecting polyurethane (PU) catheter materials were developed. Gamma radiation-induced graft copolymerization was used to functionalize PU using acrylic acid-co-glycidyl methacrylate (AAc/GMA) binary comonomer. The grafted PU, PU-g-(AAc-co-GMA), was subsequently modified by covalent immobilization of cefepime and/or wet in-situ intermatrix synthesis of ZnO (NPs) to produce PU-g-(AAc-co-GMA)/cefepime, PU-g-(AA-co-GMA-cefepime/ZnO and PU-g-(AAc-co-GMA)/ZnO nanocomposites, respectively. Modified polymers were characterized by Fourier transform infrared spectroscopy (FTIR), energy dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and scanning electron microscope (SEM). Finally, the antibacterial and antibiofilm characteristics were evaluated against five multidrug-resistant (MDR) clinical bacterial isolates; including Gram-positive and Gram-negative microorganisms. FTIR confirmed the successful grafting and subsequent immobilization of cefepime. Formation of ZnO was verified by EDX analysis, while XRD analysis revealed the crystalline nature of ZnO NPs with a size range of 43-62 nm. Moreover, SEM showed the morphology, particle size and distribution of ZnO NPs within the prepared nanocomposites. The modified PU catheter nancomposites with or without cefepime showed excellent antibacterial and anti-biofilm characteristics. The prepared polymeric biocides could be potential candidates in medical care to combat biofilm formation on biomaterials.