In this study, it was aimed to formulate linezolid loaded electrospun PLGA and PCL fiber mats doing controlled drug release, to be used in the treatment and prophylaxis of the prosthesis related infections. The effect of PLGA concentration, PLGA to PCL ratio and the amount of linezolid on the fiber and mat properties were examined. Fiber diameter has been shown to increase with increasing amount of PLGA and linezolid. Increase in PLGA amount resulted in reduced linezolid release, whereas increase in linezolid amount resulted in increased drug release. All PLGA fiber mats have shown to have favorable encapsulation efficiency (≥73%) and mechanical properties. Encapsulation efficiency and the mechanical properties deteriorated with the addition of PCL to the formulations. PLGA fiber mats have shown a biphasic controlled release and in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), pattern up to one month. The formulation selected as the optimum has been evaluated in vivo on the infected rats, which had prosthetic implantation after bone fracture. Consequently, it has been demonstrated microbiologically and histopathologically that a more efficient therapy and prophylaxis have been achieved with a 37-fold lower dose of linezolid.