Peripheral blood transcriptome is an important intermediate data source for investigating the mechanism of Salmonella invasion, proliferation, and transmission. We challenged 4-week old piglets with Salmonella enterica serovar Typhimurium LT2 and investigated the peripheral blood gene expression profile before treatment (d0) and at 2 and 7 days post-inoculation (dpi) using deep sequencing. Regulator pathways were first predicted in silico and validated by wet-lab experiments. In total, 1255, 765, and 853 genes were differentially expressed between 2 dpi/d0, 7 dpi/d0, and 7 dpi/2 dpi, respectively. Additionally, 1333 genes showed a time effect during the investigated Salmonella infection period. Clustering analysis showed that the differentially expressed genes fell into six distinct expression clusters. Pathway annotation of these gene clusters showed that the innate immune system was first significantly upregulated at 2 dpi and then attenuated at 7 dpi. Toll-like receptor cascades, MyD88 cascade, phagosome pathway, cytokine signaling pathway, and lysosome pathway showed a similar expression pattern. Interestingly, we found that the ribosome pathway was significantly inhibited at 2 and 7 dpi. Gene expression regulation network enrichment analysis identified several candidate factors controlling the expression clusters. Further in vitro study showed that TGFB1 can inhibit Salmonella replication whereas TRP53 can promote Salmonella replication in porcine peripheral blood mononuclear cells and murine macrophages. These results provide new insights into the molecular mechanism of Salmonella-host interactions and clues for the genetic improvement of Salmonella infection resistance in pigs.