Intracortical microelectrodes show large potential in helping neuroscientists further map and understand the mechanics of the brain. In addition, microelectrode technology could potentially provide the means for translating “thought” into “movement” for patients suffering from neurological deficits. However, general unreliability of microelectrode technology has halted its widespread clinical use. Further understanding of the key failure modes of intracortical microelectrodes has suggested a key role for oxidative stress in material, electrical, and biological failure modes. The overall goal of this work was to examine the role of reducing oxidative stress around implanted microelectrodes using multiple anti-oxidative approaches. In this dissertation, we report on the dynamic inflammatory responses that exist following implantation of single-shank planar microelectrode arrays and improved methodology to quantify the molecular events occurring at the microelectrode-tissue interface. We also examine multiple antioxidative approaches to (1) reduce localized reactive oxygen species accumulation, (2) prevent breakdown of the blood-brain barrier and/or (3) reduce the amount of neurodegeneration that occurs surrounding implanted microelectrodes. Of note, we observed that short term (<48 hours) administration or release of anti-oxidants could facilitate improvements in either neuronal density or viability up to two months after device implantation. Improvements in neuronal cell health were directly correlated with a localized decrease in accumulated reactive oxygen species and a more stable bloodbrain barrier. Long-term administration of anti-oxidants was able to facilitate improved neuronal viability around implanted microelectrodes, in comparison to controls, up to four months post-implantation. The results of this work further support the hypothesis that oxidative stress may facilitate the propagation of biological-mediated failure modes to intracortical microelectrodes. We anticipate that anti-oxidative approaches outlined here will be directly translational and aide in the improved reliability of microelectrode technology for use in both basic neuroscience and clinical applications.