Accumulation of reactive oxygen species (ROS) induces oxidative stress, leading to substantial damage to cellular macromolecules, necessitating efficient protein quality control mechanisms. The Lon protease, a highly conserved ATP-dependent protease, is thought to play a central role in mitigating oxidative stress by targeting damaged and misfolded proteins for degradation. This review examines the role of Lon in oxidative stress responses, including its role in degrading oxidized proteins, regulating antioxidant pathways, and modulating heme and Fe-S cluster homeostasis. We highlight cases of substrate recognition through structural changes and describe situations where Lon activity is further regulated by redox conditions. By synthesizing studies across a range of organisms, we find that despite the clear importance of Lon for oxidative stress tolerance, universal rules for Lon degradation of damaged proteins during this response remain unclear.