Clostridioides difficile infection (CDI) is a common nosocomial infection and is an urgent threat to public health. Vancomycin is the preferred antibiotic treatment for CDI but is associated with recurrence. Lactobacillus rhamnosus GG is an adjunctive treatment for gastroenteritis and diarrhea and exerts its effects by modulating the immune responses and repairing the intestinal barrier. This study explored the effect of LGG on restoring the intestinal microbiota in mouse models. Primary and recurrent CDI models were constructed, and LGG was administered to C57BL/6 mice. Structural changes in the mouse gut microbiota were determined using 16S rRNA gene analysis based on Illumina sequencing. In the CDI model, 6 days after infection, 33.3% mortality, significant weight loss and colonic injury were observed. LGG can ameliorate these events. In the R-CDI mouse model, vancomycin combined with LGG prevented weight loss, improved the histopathological scores, and effectively reduced the mortality. LGG + vancomycin administration promoted the recovery of the intestinal flora by inhibiting Enterococcus and counteracting the side effects of vancomycin treatment. In both the preventive and therapeutic CDI mouse models, the oral LGG strain showed the ability to protect against primary and recurrent infections, indicating that probiotics have potential for treating intestinal diseases. Overall, these observations suggest that LGG can be applied as a preventive treatment for CDI or in combination with antibiotics to reduce recurrence.