Shewanella oneidensis, renowned for its remarkable respiratory abilities, inhabit redox-stratified environments prone to reactive oxygen species (ROS) formation. Two major oxidative stress regulators, analogues of OxyR and OhrR, specifically respond to H2O2 and organic peroxides (OP), respectively, are encoded in the genome based on sequence comparison to well-studied models. Presumably, these analogues provide protection from ROS. An understanding of S. oneidensis OxyR has been established recently, which functions as both repressor and activator to mediate H2O2-induced oxidative stress. Here, we report the first study of elucidating molecular mechanisms underlying the S. oneidensis response to OP-induced oxidative stress. We show that S. oneidensis has OhrR, an OP stress regulator with two novel features. The sensing and responding residues of OhrR are not equally important for regulation and the regulator directly controls transcription of the SO1563 gene, in addition to the ohr gene which encodes the major OP scavenging protein. Importantly, we present evidence suggesting that the OxyR and OhrR regulons of S. oneidensis appear to be functionally intertwined as both OxyR and OhrR systems can sense and response to H2O2 and OP agents.