Conventional laboratory mice are protected from oral Campylobacter jejuni infection due to colonization resistance (CR) mediated by their host-specific gut microbiota. Here, we used differential effects of distinct antibiotics on gut microbiota composition to identify microbial groups associated with CR against C. jejuni. Therefore, specific pathogen-free (SPF) mice were subjected to ampicillin plus sulbactam (A/S), ciprofloxacin (CIP), or vancomycin (VAN) via the drinking water for 28 days or left untreated before peroral C. jejuni challenge. Cultural analyses revealed that CR displayed by untreated mice was abrogated by A/S treatment, but only reduced in mice treated with CIP or VAN. Notably, differential analysis of antibiotic-induced microbiota changes and C. jejuni colonization dynamics identified lactobacilli and Clostridium leptum as key microbial groups that were associated with CR. Notably, the complete eradication of intestinal bacteria in A/S treated mice supported high intestinal C. jejuni colonization levels which triggered apoptosis and inflammatory responses accompanied by enhanced expression of matrix-degrading gelatinases in the colon. In conclusion, A/S treated mice represent a valuable infection model for the study of campylobacteriosis and the treatment of mice with specific antibiotics support the investigation of molecular mechanisms involved in CR against enteropathogens.