In this study, we investigated the effect of Lactobacillus rhamnosus GG strain (LGG) in ameliorating enteritis in newly weaned pigs following challenge with a monophasic variant of Salmonella enterica serovar Typhimurium (serotyped as 4,,12:i:-), which has been linked to disease in humans and livestocks over the past 10 years. In weaned pigs, S. enterica serovar 4,,12:i:- induced the mRNA expression of toll like receptor (TLR) 5 and TLR4, while increasing interleukin (IL)-8 and IL-6 mRNA expression in the jejunum. The monophasic variant Salmonella stimulated the expression of nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2) mRNA in the ileum, which was accompanied by phosphorylation of IκB-α, an inhibitor of NF-κB, activating the NF-κB pathway and promoting the release of inflammatory cytokines. Oral administration of LGG attenuated the Salmonella-induced increases in the expression of NOD1 mRNA of jejunal and ileal tissues. LGG promoted the secretion of immunoglobulin A in different intestinal segments but did not induce expression of polymeric immunoglobulin receptor. LGG also impeded the activation of the Nod-like receptor protein (NLRP) 6/apoptosis-associated speck-like protein/caspase-1 inflammasome and decreased the production of IL-18 in the ileum during Salmonella infection. In contrast, activation of the NLRP3 inflammasome was not altered. Our data indicate that LGG accelerated the clearance of Salmonella in the early phase of infection and prevented the excessive inflammatory responses in S. enterica serovar 4,,12:i:- model. LGG ameliorates inflammation induced by infection with the monophasic variant Salmonella via inhibition of the canonical NF-κB pathway and attenuation of the NLRP6-mediated inflammasome in the intestine.