Hydrogen sulfide (H2S) is a gasotransmitter molecule that regulates essential plant biological processes. In the context of climate change and increasing flooding events, its role in plant responses to oxygen (O2) deficiency has gained significant attention. Accumulating evidence indicates that H2S exerts beneficial effects under hypoxia by modulating antioxidant defenses, mitochondrial function and hormonal signaling, mainly through its ability to refine protein activity via the post-translational modification (PTM) of persulfidation. Here, we discuss how this PTM is linked to the gasotransmitter molecule nitric oxide (NO) and reactive oxygen species (ROS) and how they can act synergistically or antagonistically, influencing the cell redox state and survival. Additionally, we examine how H2S turnover is intrinsically linked to O2 availability, acting as conserved mediator of low O2 responses in different domains of life. By integrating biochemical insights with molecular signaling, we underscore the potential of H2S in enhancing crop resilience to low O2 related stresses, such as submergence and waterlogging.