The aim of this study is to investigate the alleviating effect of selenium-enriched Lactobacillus plantarum (SL) 6076 on colitis and liver inflammation induced by sodium dextran sulfate (DSS) in mice and its potential molecular mechanisms. Lactobacillus plantarum (LA) was cultured for 3 generations on MRS medium containing sodium selenite to generate SL. LA (3.2 × 1011 CFU mL-1), low selenium Lactobacillus plantarum (LS) (3.9 × 1010 CFU mL-1, 0.35 mg mL-1 Se) and high selenium Lactobacillus plantarum (HS) (2.8 × 1010 CFU mL-1, 0.52 mg mL-1 Se) were continuously fed to mice for 21 d to observe their effects on DSS-induced colitis and liver inflammation in mice. The composition of gut microbiota was detected through high-throughput 16S rRNA sequencing, and inflammatory cytokines, oxidative stress parameters, and serum biochemical indicators were measured in the colon and liver using quantitative polymerase chain reaction (qPCR) and biochemical analysis methods. The results showed that SL alleviated inflammation symptoms in the colon and liver, reduced the expression of inflammatory factors in the colon and liver, regulated oxidative stress responses in the colon, downregulated NF-κB-P65 pathway factors, and altered the composition and structure of the gut microbiota. In summary, DSS-induced colitis may cause liver inflammation, and SL had a significant relieving effect on both colon and liver inflammation. The intervention effect of SL was better than that of LA, while HS was better than LS. SL had a significant alleviating effect on DSS-induced colitis, and may exert its therapeutic effect by downregulating NF-κB-P65 signaling pathways and regulating the structure of intestinal microbiota. This study provides a new approach for the treatment of colitis.