Grapes, an important and widespread fruit crop providing multiple products, face increasing flooding risks due to intense and frequent extreme rainfall. It is thus imperative to fully understand the flood-tolerance mechanisms of grapevines. Here, RNA-seq and LC-MS/MS technologies were used to analyze the transcriptome and metabolome changes in the roots of SO4 (tolerant to flooding) and Kyoho (sensitive to flooding) grapes under flooding and post-flooding conditions. The results showed that the abundance of many metabolites in the phenylpropanoids and polyketides, organic acids and their derivatives, and organic oxygen compounds superclasses changed in different patterns between the Kyoho and SO4 grapes under flooding and post-flooding conditions. Jasmonic acid and the ascorbic acid–glutathione cycle played a pivotal role in coping with both hypoxia stress and reoxygenation stress incurred during flooding and post-flooding treatments in the SO4 cultivar. Under flooding stress, the regulatory mechanistic shift from aerobic respiration to anaerobic fermentation under hypoxia is partly missing in the Kyoho cultivar. In the post-flooding stage, many genes related to ethylene, gibberellins, cytokinins, and brassinosteroids biosynthesis and brassinosteroids-responsive genes were significantly downregulated in the Kyoho cultivar, adversely affecting growth recovery; however, their expression was not reduced in the SO4 cultivar. These findings enhance our understanding of the flooding-tolerance mechanisms in grapes.