Flooding can lead to yield reduction of soybean. Therefore, identification of flooding tolerance genes has great significance in production practice. In this study, Qihuang 34, a highly-resistant variety to flooding stress, was selected for submergence treatments. Transcriptome and proteome analyses were conducted, by which twenty-two up-regulated differentially expressed genes (DEGs)/differentially expressed proteins (DEPs) associated with five KEGG pathways were isolated. The number of the DEGs/DEPs enriched in glycolysis/gluconeogenesis was the highest. Four of these genes were confirmed by RT-qPCR, suggesting that glycolysis/gluconeogenesis may be activated to generate energy for plant survival under anaerobic conditions. Thirty-eight down-regulated DEGs/DEPs associated with six KEGG pathways were identified under submergence stress. Eight DEGs/DEPs enriched in phenylpropanoid biosynthesis were assigned to peroxidase, which catalyzes the conversion of coumaryl alcohol to hydroxy-phenyl lignin in the final step of lignin biosynthesis. Three of these genes were confirmed by RT-qPCR. The decreased expression of these genes led to the inhibition of lignin biosynthesis, which may be the cause of plant softening under submergence stress for a long period of time. This study revealed a number of up-/down-regulated pathways and the corresponding DEGs/DEPs, by which, a better understanding of the mechanisms of submergence tolerance in soybean may be achieved.