Biodegradable nanofibrous hybrid membranes of polyvinyl alcohol (PVA) with ZnO and CuO nanoparticles were manufactured and characterized, and their anti-COVID-19 and anti-multidrug resistant bacteria activities were also evaluated. The morphological structures of the prepared PVA composites nanofibers were observed by scanning electron microscope (SEM), which revealed a homogenous pattern of the developed nanofibers, with an average fibrous diameter of 200–250 nm. Moreover, the results of the SEM showed that the fiber size changed with the type and the concentration of the metal oxide. Moreover, the antiviral and antibacterial potential capabilities of the developed nanofibrous membranes were tested in blocking the viral fusion of SARS-COV-2, as a representative activity for COVID-19 deactivation, as well as for their activity against a variety of bacterial strains, including multi-drug resistant bacteria (MDR). The results revealed that ZnO loaded nanofibers were more potent antiviral agents than their CuO analogues. This antiviral action was attributed to the fact that inorganic metallic compounds have the ability to extract hydrogen bonds with viral proteins, causing viral rupture or morphological changes. On the other hand, the anti-multi-drug resistant activity of the prepared nanofibers was also evaluated using two techniques; the standard test method for determining the antimicrobial activity of immobilized antimicrobial agents under dynamic contact conditions and the standard test method for determining the activity of incorporated antimicrobial agents in polymeric or hydrophobic materials. Both techniques proved the superiority of the ZnO loaded nanofibers over the CuO loaded fibers. The results of the antiviral and antibacterial tests showed the effectiveness of such nanofibrous formulas, not only for medical applications, but also for the production of personal protection equipment, such as gowns and textiles.