Background/Objectives: Enteropathogenic Escherichia coli O157:H7 infection disrupts intestinal homeostasis, causing dysbiosis, barrier dysfunction, and inflammation. This study aimed to evaluate the protective efficacy and mechanisms of a novel probiotic, Bacteroides thetaiotaomicron type strain ATCC 29148, isolated from goat feces, against E. coli O157:H7-induced colitis. Methods: This study assessed the protective potential of the probiotic strain Bacteroides thetaiotaomicronBT6 and BT7 in vitro for GI tolerance, adhesion, and no adverse effects were observed. For the in vivo experiment, male C57BL/6J mice were divided into groups treated with Bacteroides thetaiotaomicron (BT6), PBS, E. coli O157:H7, or a combination. We employed integrated analyses including 16S rRNA gene sequencing, antioxidant status, cytokine profiling, and short-chain fatty acid (SCFA) measurement. Results: In vitro, Bacteroides thetaiotaomicron (BT6 and BT7) showed high gastrointestinal tolerance (71.89–93.22% survival). In vivo, it significantly mitigated infection-associated weight loss and disease activity (p < 0.05). Probiotic treatment enhanced barrier integrity, reduced colonic inflammation, and modulated systemic immune responses, notably increasing anti-inflammatory IL-10 while decreasing pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 (p < 0.05). It also alleviated oxidative stress by reducing malondialdehyde (MDA) and elevating antioxidant enzymes (SOD, CAT, GSH) and ATP. Fecal SCFA profiling revealed increased propionic and butyric acid. 16S sequencing indicated that B. thetaiotaomicron (BT6) administration increased beneficial families (Lactobacillaceae, Muribaculaceae) and suppressed pathobionts. Conclusions: B. thetaiotaomicron (BT6) probiotic with potential for mitigating enteropathogenic infection, an effect mainly determined by its capacity to reestablish the intestinal epithelial barrier and enhance global host health, and modulating the inflammatory response.