Formaldehyde is a common indoor and outdoor air pollutant that adversely impacts global public health. Many toxicological studies have shown that formaldehyde causes nasopharyngeal cancer, possibly through tissue damage, increased cell proliferation, and/or DNA damage. However, there is lack of knowledge regarding formaldehyde's effects at the systems biology level and whether epigenetic mechanisms may contribute to cellular responses. Furthermore, whether formaldehyde is capable of altering genomic and epigenomic processes throughout sites distal to the respiratory tract is unknown. This topic is of high interest, as the link between formaldehyde inhalation exposure and leukemia development is currently under heated debate. Epidemiological studies have shown evidence supporting a link between formaldehyde exposure and leukemia development, while toxicological investigations have yet to provide evidence supporting formaldehyde's ability to influence sites distant to the respiratory tract. Before this dispute is resolved, further evaluation of the biological mechanisms linking formaldehyde to disease is clearly necessary. In particular, formaldehyde-induced changes to epigenetic contributors to transcriptional programs are extremely understudied, where microRNA (miRNA) expression profiles have yet to be investigated in relation to formaldehyde. We set out to test the novel hypothesis that miRNAs have altered expression profiles within the respiratory and hematopoietic systems upon exposure to formaldehyde. Our studies were the first to show that formaldehyde significantly disrupts miRNA expression patterns in vitro, within cultured human lung cells, and in vivo, within the nasal epithelium of nonhuman primates. Using a rodent model, the impact of formaldehyde exposure on miRNA-related processes in direct contact and distant tissues, including the nasal mucosa, circulating white blood cells, and bone marrow, was evaluated. Formaldehyde was found to significantly alter miRNA expression profiles within the nose and blood, but not the bone marrow. Evaluating the epigenetic effects of formaldehyde exposure at the systems biology level, putative miRNA-mediated responses were mapped onto interacting networks. Signaling related to inflammation, cell death, and cancer was identified as enriched. Taken together, our research increases the knowledge of under-studied mechanisms linking formaldehyde exposure to disease, acting as an important foundation for future research in public health and toxicology.