In this study we employed an in vivo approach coupled to 2D-DIGE and microarrays analysis to explore the response of porcine mesenteric lymph nodes (MLN) to S. Typhimurium infection at genomic and proteomic levels. MLN samples were collected from four control and twelve infected pigs (at 1, 2 and 6 days post infection) for protein and RNA purification. Protein was screened by differential in gel analysis and changes in transcriptome were assessed by Bayesian Analysis of Time Series. Afterwards, bioinformatic tools were employed to analyse and integrate data from both strategies. Comparison of genomic and proteomic data uncovered unique enriched mechanisms from each methodology. However, common functional changes were also observed, highlighting “Antigen processing and presentation” as the most significantly altered pathway in both approaches. Since both methodologies confirmed the induction of this mechanism in porcine MLN upon S. Typhimurium infection, we stress molecules taking part in this route as candidates for studies focusing on the genetic improvement of Salmonella resistance in pigs.