To study the effect of tropomyosin of Macrobrachium nipponense on macrophage polarization, the differential analysis of gene expression during tropomyosin-induced macrophage polarization was analyzed by transcriptomic analysis. The results showed that compared with the phosphate buffer saline group (PBS group), 69 genes were up-regulated and 154 genes were down-regulated in the tropomyosin-induced group (TM group), and 180 pathways were enriched. In the lipopolysaccharide and IFN-γ combined-induced M1 macrophage group(LPSIFN group), 1346 genes were up-regulated, 1360 genes were down-regulated, and 308 pathways were enriched. Compared with the IL-4-induced M2 macrophage group(IL4 group), 455 genes were up-regulated in the TM group, 446 genes were down-regulated and enriched to 269 pathways. According to the KEGG results, five signaling pathways that may be involved in macrophage polarization were selected, including NOD-like receptor signaling pathway, Jak-STAT signaling pathway, NF-κB signaling pathway, Toll-like receptor signaling pathway and PI3K/Akt signaling pathway. The expression of NOD2, TLR2, AKT3, NLRP3, Caspase-1, CD14, Lat, Myd88, NFKBIA and STAT1 genes in these five pathways were verified, and the expression levels of NOD2, TLR2, NLRP3, and STAT1 in the TM group were increased significantly. The NOD-like receptor signaling pathway, Jak-STAT signaling pathway, and Toll-like receptor signaling pathway related to these four genes were involved in the process of tropomyosin-induced macrophage polarization. The purpose of this study was to provide a theoretical basis for the further analysis of the relationship between macrophage polarization and food allergic relationships.