Implantable drug-delivery systems provide new means for achieving therapeutic drug concentration over a prolonged time to achieve better tissue protection and enhanced recovery. The hypothesis of the current study was to test the antioxidant and anti-inflammatory effects of genistein and nanofibers on the spinal cord tissue following experimental spinal cord injury (SCI). Rats were treated post SCI with genistein loaded on chitosan/polyvinyl alcohol (CS/PVA) nanofibers as an implantable drug-delivery system. SCI caused marked oxidative damage and inflammation as evident by the reduction in the super oxide dismutase (SOD) activity and the level of interleukin-10 (IL-10) in injured spinal cord tissue, as well as, the significant increase in the levels of nitric oxide (NO), malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α). Treatment of rats post SCI with genistein and CS/PVA nanofibers improved most of the above mentioned biochemical parameters and shifted them toward the control group values. Genistein induced an increase in the activity of SOD and the level of IL-10, while causing a decrease in the levels of NO, MDA and TNF-α in injured spinal cord tissue. Genistein and CS/PVA nanofibers provide a novel combination for treating inflammatory nervous tissue conditions, especially when combined as an implantable drug-delivery system.