Soybean (Glycine max) was domesticated from its wild relative Glycine soja. However, the genetic variations underlying soybean domestication are not well known. Comparative transcriptomics revealed that a small portion of the orthologous genes might have been fast evolving. In contrast, three gene expression clusters were identified as divergent by their expression patterns, which occupied 37.44% of the total genes, hinting at an essential role for gene expression alteration in soybean domestication. Moreover, the most divergent stage in gene expression between wild and cultivated soybeans occurred during seed development around the cotyledon stage (15 d after fertilization, G15). A module in which the co-expressed genes were significantly down-regulated at G15 of wild soybeans was identified. The divergent clusters and modules included substantial differentially expressed genes (DEGs) between wild and cultivated soybeans related to cell division, storage compound accumulation, hormone response, and seed maturation processes. Chromosomal-linked DEGs, quantitative trait loci controlling seed weight and oil content, and selection sweeps revealed candidate DEGs at G15 in the fruit-related divergence of G. max and G. soja. Our work establishes a transcriptomic selection mechanism for altering gene expression during soybean domestication, thus shedding light on the molecular networks underlying soybean seed development and breeding strategy.