Louis Pasteur first reported that living cells switch from aerobic to anaerobic metabolism under low-oxygen conditions. We searched for Arabidopsis thaliana mutants with downregulated expression of hypoxia-induced ALCOHOL DEHYDROGENASE 1 (ADH1), encoding a key enzyme in ethanolic fermentation. This screen identified mutants in IQ DOMAIN containing protein 22 (IQD22). The iqd22 mutants were hypersensitive to submergence and hypoxic stress, whereas IQD22 overexpressors were more tolerant of both compared to wild type. Moreover, under hypoxia, IQD22 interacted with calmodulins (CaMs) in vivo and facilitated their association with ADH1, stimulating its activity. Metabolic profiling revealed that hypoxia caused significant increases of glycolytic metabolites, but significantly lower ethanol in iqd22-2 mutant compared to the wild type. Furthermore, deleting ADH1 suppressed the improved hypoxia-tolerance phenotype of IQD22 overexpressors. Our findings thus shed light on the IQD22–CaM–ADH1 regulatory module that mediates calcium-dependent activation of anaerobic respiration to control metabolic flux during hypoxia.