Oxygen (O₂) deprivation, or hypoxia, has profound effects on cell metabolism and growth. Cells can adapt to low O₂ in part through activation of hypoxia-inducible factor (HIF). We report here that hypoxia inhibits mRNA translation by suppressing multiple key regulators, including eIF2α, eEF2, and the mammalian target of rapamycin (mTOR) effectors 4EBP1, p70^S6K, and rpS6, independent of HIF. Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR pathway. Hypoxic AMP-activated protein kinase (AMPK) activation also leads to eEF2 inhibition. Moreover, hypoxic effects on cellular bioenergetics and mTOR inhibition increase over time. Mutation of the TSC2 tumor suppressor gene confers a growth advantage to cells by repressing hypoxic mTOR inhibition and hypoxia-induced G₁ arrest. Together, eIF2α, eEF2, and mTOR inhibition represent important HIF-independent mechanisms of energy conservation that promote survival under low O₂ conditions.