Abstract The aim of this study was to evaluate the efficacy of two probiotic strains Bifidobacterium longum subsp. infantis CECT7210 (Laboratorios Ordesa S.L.) and Lactobacillus rhamnosus HN001 combined or not with a prebiotic mixture of oligofructose and inulin against Salmonella typhimurium. A total of 96 piglets (28 days) were distributed into 32 pens assigned to 5 treatments: one non-challenge (control diet, CTR+) and four challenged: control diet (CTR-), or supplemented with probiotic (>3x1010cfu/kg each, PRO), prebiotic (5%, PRE) or their combination (SYN). After one adaptation week, animals were inoculated with Salmonella. Feed intake, weight and clinical signs were recorded. On days 4 and 8 post-inoculation (PI), one animal per pen was euthanized and samples collected for Salmonella counts, fermentation products, ileal histomorphology and serum inflammatory markers. After the challenge, feed intake was decreased (P = 0.001) more markedly in the SYN group with a lower final weight (P = 0.009). PRE and SYN groups showed more liquid ileal consistency on day 8PI (P = 0.009). A higher percentage of animals receiving PRO became negative to Salmonella in feces at the end of the study (65% PRO vs 0% CTR-, P = 0.028). Animal receiving PRE did not reach countable levels in feces any time during the trial (vs 23.2% for CTR-group, P = 0.013). Histologically, on day 4PI a decrease in the ileal villous/crypts ratio was found in challenged animals (P < 0.001), being PRO able to improve the recovery from this damage at day 8PI (P = 0.008). Animals receiving PRE had higher number of intraepithelial lymphocytes (IEL) on day 8PI (P = 0.028). In conclusion, the probiotic strains were able to promote a faster clearance of the pathogen from the gut with a faster recovery of damaged histological architecture. The prebiotic reduced Salmonella colonization and stimulated the local immune response. However, these beneficial effects disappeared when they were administered in a synbiotic form.