Nutrients are not only organic compounds fueling bioenergetics and biosynthesis, but also key chemical signals controlling growth and metabolism. Nutrients enormously impact the production of reactive oxygen species (ROS), which play essential roles in normal physiology and diseases. How nutrient signaling is integrated with redox regulation is an interesting, but not fully understood, question. Herein, we report that superoxide dismutase 1 (SOD1) is a conserved component of the mechanistic target of rapamycin complex 1 (mTORC1) nutrient signaling. mTORC1 regulates SOD1 activity through reversible phosphorylation at S39 in yeast and T40 in humans in response to nutrients, which moderates ROS level and prevents oxidative DNA damage. We further show that SOD1 activation enhances cancer cell survival and tumor formation in the ischemic tumor microenvironment and protects against the chemotherapeutic agent cisplatin. Collectively, these findings identify a conserved mechanism by which eukaryotes dynamically regulate redox homeostasis in response to changing nutrient conditions. Display omitted •SOD1 is a conserved effector of mTORC1 signaling in eukaryotic cells•Nutrients restrain SOD1 through mTORC1-dependent phosphorylation to promote growth•Starvation stimulates SOD1 activity to prevent oxidative damage and enhance survival•SOD1 enhances cancer cell survival and chemoresistance in ischemic microenvironment Tsang et al. show that SOD1 phosphorylation by mTOR provides a dynamic mechanism for eukaryotic cells to respond to changing nutrient conditions. It permits rapid growth in rich nutrients, while it confers resistance to oxidative stress during starvation. This mechanism contributes to cancer cell survival and chemoresistance in the ischemic microenvironment.