This study aimed to explore the protective effect and potential mechanism of Nostoc commune Vauch. polysaccharide (NCVP) on lead (Pb)-poisoning mice. NCVP improved Pb-induced hepatorenal toxicity and inflammatory responses and modulated key indicators of antioxidant capacity. Moreover, the down-regulation of critical proteins of the Nrf2 pathway induced by Pb could be reversed after NCVP intervention. In addition, NCVP maintained the diversity of gut bacteriobiota and restored the relative abundance of f_Prevotellaceae, g_Alloprevotella, and f_Eubacterium_coprostanoligenes_group reduced by Pb. Also, NCVP regulated the diversity and abundance of gut mycobiota affected by Pb. Specifically, Pb decreased the proportion of pathogenic species (g_Fusarium, p_Basidiomycota, g_Alternaria, g_Aspergillus, and g_Candida) while NCVP increased the abundance of probiotics species (g_Kazachstania and p_Ascomycota). Furthermore, the metabolomic analysis found that NCVP significantly altered a range of microbial metabolites, including porphobilinogen, cromakalim, salidroside, and trichostatin A, which has significant associations with specific gut bacteriobiota or mycobiota. These altered metabolites are involved in primary bile acid biosynthesis, metabolism of xenobiotics by cytochrome P450, lysine degradation, and other metabolic pathways. Overall, our findings indicate that NCVP might be an excellent natural product for eliminating Pb-induced hepatorenal toxicity, possibly by regulating gut bacteriome, mycobiome and metabolome.