Lead (Pb) is a hazardous heavy metal with no known safe threshold for exposure or consumption, posing significant risks to human health. Pb exposure can cause multiple system damage, depending on exposure levels, duration, and its high bioavailability and bioaccumulative potential. Gastrointestinal tract serves as a primary site for Pb absorption, making it particularly vulnerable to Pb-induced damage, including disruption of gut microbiota composition and metabolic function. This study briefly summarizes the detrimental effects of Pb gut homeostasis, microbial ecology, and host metabolism, which, in turn, further contribute to systemic toxicity. Notably, Pb exposure compromises intestinal barrier integrity, increasing gut permeability and facilitating the translocation of harmful biomolecules into systemic circulation, thereby exacerbating organ dysfunction. Importantly, we underscore that dietary and nutritional interventions such as fiber, probiotic, and vitamin C supplementation is a practicable and effective strategy for mitigating or preventing Pb toxicity.