Hypoxia is an important stress for organisms, including plants and mammals. In plants, hypoxia can be the consequence of flooding and causes important crop losses worldwide. In mammals, hypoxia stress may be the result of pathological conditions. Understanding the regulation of responses to hypoxia offers insights into novel approaches for crop improvement, particularly for the development of flooding-tolerant crops and for producing better therapeutics for hypoxia-related diseases such as inflammation and cancer. Despite their evolutionary distance, plants and mammals deploy strikingly similar mechanisms to sense and respond to the different aspects of hypoxia-related stress, including low oxygen levels and the resulting energy crisis, nutrient depletion, and oxidative stress. Over the last two decades, the ubiquitin/proteasome system and the ubiquitin-like protein SUMO have been identified as key regulators that act in concert to regulate core aspects of responses to hypoxia in plants and mammals. Here, we review ubiquitin and SUMO-dependent mechanisms underlying the regulation of hypoxia response in plants and mammals. By comparing and contrasting these mechanisms in plants and mammals, this review seeks to pinpoint conceptually similar mechanisms but also highlight future avenues of research at the junction between different fields of research.