The rise of antimicrobial resistance represents an escalating global health emergency, with the human gut microbiome playing a pivotal and dualistic role. While a healthy microbiota provides essential immune support and colonization resistance, antibiotic misuse triggers dysbiosis, turning the gut into a “resistome” that facilitates the spread of resistance genes. This article examines the “friend or foe” paradigm, arguing that maintaining microbial stability is key to mitigating resistance. By leveraging a “One Health” approach and innovative strategies such as personalized medicine, phage therapy, and microbiome-targeted therapies, the researchers and policymakers can harness the gut’s protective potential to combat multidrug-resistant pathogens and secure long-term therapeutic efficacy.