Environmental factors, infection, or injury, cause oxidative stress in diverse tissues, resulting in immune activation and loss of tissue homeostasis. Effective stress response cascades, conserved from invertebrates to mammals, ensure reestablishment of homeostasis and tissue repair. Plasmatocytes, the Drosophila macrophage-like cells, are thought to respond to oxidative stress by immune activation, however the signaling cascades involved in oxidative stress sensing and subsequent immune activation are yet to be defined. Furthermore, their role in modulating and controlling oxidative stress response to facilitate tissue repair and survival of the organism is not resolved. Here we describe the responses of hemocytes in adult Drosophila to oxidative stress and the essential role of non-canonical DNA damage repair activity in direct “responder” hemocytes to control JNK-mediated stress signaling, systemic levels of the cytokine upd3 and subsequently susceptibility to oxidative stress. Our results point to an essential systemic role of hemocytes in controlling systemic oxidative stress response in Drosophila, including energy mobilization for potential tissue repair.