Abstract: Inorganic arsenic (iAs), a widespread environmental contaminant, enters the human body through drinking water, the food chain, and air inhalation. During iAs metabolism, the key signaling axis AS3MT/c-Fos plays a central role, driving genotoxicity through the regulation of non-coding RNAs (ncRNAs) and epigenetic modifications, thereby inducing adverse health outcomes such as skin lesions and malignancies. This review systematically summarized the metabolic mechanisms of iAs within the microenvironments of the respiratory and gastrointestinal microbiomes and their interactions with microbial community structures. iAs exposure reduces the abundance of Firmicutes and increases Proteobacteria in the gut microbiota, while concurrently suppressing antimicrobial functions in the respiratory microbiota. The iAs-induced dysbiosis triggers a cascade of epigenetic alterations, including changes in DNA methylation, post-translational histone modifications, and the expression and function of microRNAs (miRNAs), promoting cell proliferation and carcinogenesis. Furthermore, iAs exposure induces microbial metabolite butyrate, which cooperatively regulates the expression of the proto-oncogene c-Fos (Fos) through multi-faceted mechanisms. Additionally, bidirectional communication via the gut-lung axis, mediated by microbial metabolites such as short-chain fatty acids (SCFAs), disrupts immune homeostasis in distal organs, exacerbating the risk of iAs-associated cancers. This review aims to integrate current knowledge within the field, seeking to deepen the understanding of iAs-induced toxicity and carcinogenesis mechanisms, and to provide a scientific foundation and innovative insights for developing effective prevention and treatment strategies against iAs-related diseases.