The application of non-thermal (cold) plasmas in medicine holds great promise. Non-thermal plasma devices have been used to directly ablate cells, induce apoptosis, facilitate cell transfection, lay down bioscafolds, and sterilize heat sensitive materials. Although the reactive species (RS) generated by the plasmas have been implicated in all of these processes, the biological mechanisms of action are poorly understood and the potential adverse effects largely unknown. In this work, we used a parallel electrode dielectric barrier discharge (DBD) and the atmospheric pressure glow discharge torch (APGD-t) to assess the possible negative effects of direct and indirect plasma treatment of mammalian cells and naked DNA. He La cells demonstrated an oxidative stress response when placed in direct contact with the plasma. No lipid peroxidation resulted from the application of the plasma to the cells. Both plasma sources were shown to be able to fragment naked DNA in PBS and to cause DNA double-strand breaks (DSBs). Sequencing of treated plasmid DNA introduced into electrocompetent bacterial cells showed no evidence of mutations. We conclude that the reactive nature of non-thermal plasmas can create oxidative stresses and may have unintended negative biological effects on cells.