Climate change is increasing the frequency and severity of heatwaves, posing a significant threat to aquatic organisms globally. During an extended heatwave, aquatic organisms, like fish, may use phenotypic plasticity to help offset the effects of increased temperatures and associated low oxygen. The ability of a population to use plasticity to cope with heatwaves could be key for predicting species responses to climate change, especially in species of conservation concern like white sturgeon. We assessed the tolerance of juvenile white sturgeon from an endangered population to heatwave conditions and the effects of heatwave acclimation on subsequent stressors. We measured both thermal and hypoxia performance paired with underlying epigenetic and transcriptional mechanisms to assess the resilience of white sturgeon to heatwaves. Sturgeon exposed to simulated heatwave conditions had increased thermal tolerance and showed complete compensation for the effects of acute hypoxia. These changes were associated with increases in mRNA levels of genes associated with thermal and hypoxic stress. Global DNA methylation was sensitive to heatwave acclimation, changing in the gill and heart over the course of the heatwave exposure. Additionally, we observed rapid changes in DNA methylation during stressor trials over the course of an hour. These data demonstrate tremendous resilience in juvenile white sturgeon to heatwaves which was associated with improved cross-tolerance and responses in epigenetic and transcriptional mechanisms.