Background <p>German cockroaches (<i>Blattella germanica</i>) are prevalent indoor pests that have long been associated with the spread of enteric human pathogens. Recent work investigating the relationship between these insects and <i>Salmonella enterica</i> serovar Typhimurium (<i>S.</i> Typhimurium), a model pathogen of global concern, demonstrated that <i>S.</i> Typhimurium colonizes the cockroach gut. <i>S</i>. Typhimurium has a broad host range, but mechanistic molecular insight into how ecologically relevant invertebrate hosts interact with this pathogen is lacking. Here, we applied a multi-omic (transcriptomic and proteomic) approach to infected cockroaches to examine the molecular variables that govern cockroach-borne <i>S.</i> Typhimurium transmission.</p> Results <p>Our results reveal enriched monocarboxylic acid transport and metabolism, increased long-chain fatty acid transport, increased triglyceride metabolism, and an increased response to reactive oxygen species and free radicals as host signatures of a metabolic shift in the cockroach gut during infection. Surprisingly, downregulation of the immune deficiency (IMD) pathway transcription factor relish, and upregulation of xenobiotic detoxification (glutathione-s-transferase) and known allergens (Blag5 &amp; Blag8, myosin, tropomyosin) were also evident in infected guts.</p> Conclusions <p>To our knowledge, this study is both the first omics study of enteric human pathogen infection in a cockroach vector and the first omics study of <i>S.</i> Typhimurium in an ecologically relevant insect host, representing a seminal contribution to the field of vector-borne infectious disease. This work provides novel fundamental knowledge regarding the response of insect hosts to <i>S.</i> Typhimurium infection and the evolution of vector-pathogen relationships with the potential to inform mitigation of the public health impacts of cockroaches.</p>