A westernized diet characterized by high fat and sugar is tightly associated with the development of metabolic diseases and inflammatory bowel disease. Although a high-fat diet has been extensively studied for its involvement in various diseases, fewer studies have examined the impact of a high-sugar diet on the development of certain diseases, particularly enteric infections. This study aimed to explore the effect of a high sucrose diet on Salmonella Typhimurium-induced infection. C57BL/6 mice received a normal diet (Control) or a high sucrose diet (HSD) for eight weeks and then were infected by Salmonella Typhimurium. The high-sugar diet profoundly altered the relative abundance of certain microbial taxa. Bacteroidetes and Verrucomicrobiota were more abundant in normal diet-fed mice than in HSD-fed mice. Moreover, short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs) were significantly higher in mice from the control group than the HSD group. More S. Typhimurium counts in feces and other tissues were observed in HSD-fed mice after infection. Tight junction proteins and antimicrobial peptides were significantly decreased in HSD-fed mice. Fecal microbiota transplantation (FMT) demonstrated that mice that received normal fecal microbiota had lower Salmonella Typhimurium burdens compared with mice that received HSD fecal microbiota, indicating that the altered microbial communities are associated with the severity of infection. Together, these findings suggest that the excessive intake of sucrose disturbs intestinal homeostasis and predisposes mice to Salmonella-induced infection.