Controlled brain injuries in mice revealed that brief antibiotic courses decreased lesion volumes by disrupting gut bacteria, with the most dramatic neuroprotective effects observed after repeat injuries. Antibiotic-treated animals showed reduced microglial activation, lower inflammatory cytokine production, and less astrogliosis compared to untreated controls, despite having depleted gut microbiomes and reduced short-chain fatty acid production. This finding challenges conventional thinking about gut-brain axis therapeutics, which typically emphasize microbiome preservation rather than targeted disruption. The protective mechanism appears independent of beneficial microbial metabolites like SCFAs, suggesting that removing specific inflammatory bacteria may outweigh losing protective ones in acute brain trauma. Germ-free mice paradoxically suffered worse outcomes, indicating some microbial presence remains necessary. Two bacterial species, Parasutterella excrementihominis and Lactobacillus johnsonii, survived antibiotic treatment and may represent key protective organisms. The research has immediate clinical relevance since antibiotics are commonly prescribed following traumatic brain injuries to prevent secondary infections, yet their neurological effects remain understudied. This work suggests judicious antibiotic use might serve dual purposes in TBI patients, though the optimal timing, duration, and bacterial targets require careful investigation before clinical implementation.