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Mitochondria are key intracellular targets of hypoxia-reoxygenation (H/R) stress due to their central role in generation of ATP and reactive oxygen species (ROS). Intertidal oysters Crassostrea gigas are adapted to frequent H/R cycles and maintain aerobic function despite frequent oxygen fluctuations. To gain insight into the molecular mechanisms of H/R tolerance, we assessed changes in mitochondrial respiration and (phospho)proteome of C. gigas during hypoxia and recovery. Oyster mitochondria maintained OXPHOS capacity despite a decline in cytochrome c oxidase activity during H/R stress. Rearrangements of the mitochondrial proteome during H/R stress involved upregulation of mitochondrial electron transport system and iron-binding proteins, and suppression of the pathways that channel electrons to ubiquinone, possibly as a mechanism to limit ROS production. H/R stress led to upregulation of a mitophagic activator PGAM5 and dephosphorylation of metalloendopeptidase OMA1, indicating stimulation of mitochondrial quality control mechanisms. Changes in abundance and phosphorylation levels of key proteins involved in mitochondrial protein homeostasis indicate suppression of protein synthesis during hypoxia, likely as an energy-saving mechanism, and its subsequent reactivation during reoxygenation. Thus, shifts in the mitochondrial (phospho-)proteome might play an important role in H/R stress resistance of oysters ensuring mitochondrial integrity and function during oxygen fluctuations. SIGNIFICANCE: Hypoxia-reoxygenation (H/R) stress elicits shifts in proteome and phosphoproteome of mitochondria in a hypoxia-tolerant model bivalve, oyster Crassostrea gigas, upregulating electron transport system, limiting electron flow to ubiquinone and activating mitochondrial quality control and protein homeostasis mechanisms. These findings provide insights into the potential role of proteomic shifts in adaptive response to H/R stress and serve as an important benchmark to understand the mechanisms of mitochondrial sensitivity to hypoxia and reoxygenation.