Mitochondrial oxidative damage contributes to a wide range of pathologies, including ischemia/reperfusion (I/R) injury, cardiovascular disorders and neurodegenerative diseases. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel kyotorphin-nitroxide hybrid molecules, and examined their free radical scavenging activities, in addition to their anti-inflammatory and analgesic activities. We have further characterized these compounds in a simulated I/R cellular model. Our findings suggest that the protective effects of kyotorphin-nitroxides partially reside in maintaining optimal mitochondrial function.