Louis Pasteur first reported that living cells switch from aerobic to anaerobic metabolism under low-oxygen conditions, but the underlying regulatory mechanism remains to be fully elucidated. ALCOHOL DEHYDROGENASE 1 (ADH1) encodes a key enzyme in ethanolic fermentation and is upregulated under hypoxia. In this study, we searched for Arabidopsis thaliana mutants with defects in hypoxia-induced ADH1 expression and identified the IQ DOMAIN containing protein 22 (IQD22) as a crucial regulator of ADH1-mediated hypoxia tolerance. The iqd22 mutant plants were hypersensitive to submergence and hypoxic stress as compared with the wild-type plants, whereas IQD22 overexpressors were more tolerant. We showed that under hypoxia, IQD22 enhances the interaction between the calcium-dependent protein kinase CPK12 and the ETHYLENE RESPONSE FACTOR (ERF)-VII-type transcription factor RELATED TO AP2.12 (RAP2.12) to upregulate hypoxia-responsive genes, including ADH1. Moreover, we found that IQD22 interacts with calmodulins (CaMs) in vivo and facilitates their association with ADH1, stimulating its abundance in response to hypoxia. Metabolic profiling revealed that hypoxia causes significant increase in glycolytic metabolites but greatly lower ethanol accumulation in the iqd22-2 mutant. Genetic analysis showed that disruption of ADH1 suppresses the improved hypoxia-tolerance phenotype of IQD22 overex-pressors. Taken together, these results indicate that IQD22 functions in the CaM-ADH1 and CPK12-RAP2.12 regulatory modules, which coordinately mediate calcium-dependent activation of anaerobic respiration to control metabolic flux during hypoxia.