Cold atmospheric pressure plasma (ionized gas) is an innovative medical tool for the treatment of infected wounds thanks to its potential to inactivate drug-resistant microorganisms and promote tissue regeneration and vascularization. The low power consumption, compactness, and versatility of Cold Atmospheric Pressure Plasma (CAPP) devices make them an ideal tool for risk mitigation associated with human spaceflights. This work presents results in microgravity on the operability of CAPP and its antimicrobial effect. The experiments carried out in parabolic flights make it possible to optimize the treatment conditions (i.e., the distance, the gas mixture) and to obtain the rapid inactivation (<15 s) of Escherichia coli samples. Interestingly, the inactivation efficiency of CAPP was higher during parabolic flights than under terrestrial conditions. Overall, these results encourage the further development of CAPP medical devices for its implementation during human spaceflights.