Global climate change influences the magnitude and frequency of hydrological fluctuations and causes an unfavorable environment for plant growth and development. Food shortages are one of the most serious global problems in this century, and it is important to increase food production. Soybean, which is rich in protein and vegetable oil, is cultivated in several climatic zones; however, its growth is markedly decreased due to flooding. On the other hand, smoke is used in traditional farming systems for improving seed germination and seedling vigor. To clarify the mechanism of flooding tolerance in early-stage soybean, plant-derived smoke was applied, which exhibited a flooding tolerant phenotype. The growth of soybean seedlings was suppressed under flooding stress, but it recovered after water removal following treatment with plant-derived smoke. Early-stage soybeans treated with plant-derived smoke under flooding stress were collected for gel-free/label-free proteomic, RNA-sequencing based transcriptomic, and mass-spectrometry based metabolomic analyses. Data sets were analyzed using functional categorization/cluster separation; furthermore, enzyme-activity, immuno-blot, and gene-expression experiments were performed to confirm the data acquired from comprehensive analyses. These results suggest that plant-derived smoke protects newly synthesized proteins via ribosomal protein and enhancing the activities of antioxidative enzymes to remove reactive-oxygen species. Furthermore, an integrated approach of proteomics with computational genetic modification effectiveness analysis was applied to explore flood-tolerant genes in soybean, suggesting that proteins related to energy metabolism might play an essential role to confer flood tolerance in soybeans.