Several of the most prevalent forms of cancer and neurodegenerative disease are linked to chronic low dose pesticide exposure. Low-dose pesticide exposure occurs daily for over 100M Americans. Children exposed to pesticides are twice as likely to develop brain cancer as those unexposed, and mothers exposed to organochlorine pesticides have children with six-fold increased risk for autism spectrum disorders. We model pesticide-induced human disease using chronic exposures in Drosophila. Pathways targeted by pesticides exist in off-target organisms, including gut microbes, and low dose exposures may result in microbiome-mediated adverse health outcomes. Ingested chemicals are metabolized, and exposure involves all secondary and tertiary host and microbial metabolites, which may exhibit emergent or compound toxicity. The commensal microbiome of the Drosophila gut constitutes an exquisitely simplified model system in which to study the molecular basis of low-dose pesticide susceptibility and resiliency. We used a multi-omics approach (RNA-seq, metabolomics, 16S and metagenomics, phenomics) to study the modes of actions of three widely used herbicides, atrazine, glyphosate and paraquat on fly health. As controls, we studied cadmium chloride (positive control), WY14643 (vertebrate-specific drug, negative control), and alcohol (negative control). All three herbicides radically reshape the gut microbiome community compositions at environmentally relevant doses, and induce concomitant alterations in the fecal metabolome. Cadmium chloride, in contrast, had toxic effects for the host, but no statistically significant action on the gut microbiome. Whole genome PacBio sequencing of gut microbes identifies thousands of new microbial genes, and provides insights into the molecular basis of microbiome remodeling in response to pesticide exposures. Integration with host transcriptomics reveals adaptive responses to atrazine and glyphosate, which are both fully metabolized and undetectable in the feces, and more pronounced stress response to paraquat. Analysis of differentially expressed genes indicates that glyphosate acts as an endocrine disruptor in flies, while atrazine may modify lipid and cholesterol transport and metabolism. Paraquat eliminates Acetobacter in the gut, while atrazine and glyphosate both serve as prebiotics for several microbial clades – increasing population frequencies of basally rare families. The genes modulated by paraquat and atrazine are deeply conserved across the metazoan phylogeny and human. Machine learning on behavioral imaging data identifies phenotypes at all tested dosages, interpretable as lack of coordination – consistent with neurological disease. We predict that epidemiological studies of human populations exposed to Atrazine (33M Americans) will show increased incidence of neuromuscular disease.