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This study investigated the effects of a short-term administration of bovine colostrum (BC) in a TNBS model of induced colitis. Colitis was induced by TNBS treatment after seven days of BC (BC group, n = 12) or saline (control group, n = 12) administration in mice. Clinical signs, histopathological characteristics, expression levels of Toll-like receptor 4 (TLR4), pro- and anti-inflammatory cytokines, and microbial composition were assessed. BC was well tolerated and did not induce any histological damage or clinical symptoms. After TNBS treatment, the BC group showed a reduction in body weight (BW) loss compared to Control (<i>p</i> &lt; 0.05). Moreover, expression levels of TLR4 (<i>p</i> &lt; 0.01), Interleukin-1&#946; (IL-1&#946;; <i>p</i> &lt; 0.001), Interleukin-8 (IL-8; <i>p</i> &lt; 0.001), and Interleukin-10 (IL-10; <i>p</i> &lt; 0.001) were lower in mice administered with BC. Finally, <i>Escherichia coli</i> were higher (<i>p</i> &lt; 0.05), while Enterococci (<i>p</i> &lt; 0.001), <i>Lactobacillus</i> spp. (<i>p</i> &lt; 0.001), and <i>Bifidobacterium</i> spp. (<i>p</i> &lt; 0.05) were lower in Control than BC group. This study confirms that pre-treatment with BC modulates the expression of genes and the count of microbes involved in the etiopathogenesis of colitis.