BACKGROUND: Bed bugs are blood-feeders that rapidly proliferate into large indoor infestations. Their bites can cause allergies, secondary infections and psychological stress, among other problems. Although several tactics for their management have been used, bed bugs continue to spread worldwide wherever humans reside. This is mainly due to human-mediated transport and their high resistance to several classes of insecticides. New treatment options with novel modes of action are required for their control. In this study, we evaluated the use of nitisinone (NTBC), an FDA-approved drug, for bed bug control in an insecticide-susceptible (HH) and an insecticide-resistant (CIN) population. RESULTS: Although NTBC was lethal to both populations when administered orally or applied topically in very low doses, we observed a slight but significant resistance in the CIN population. Transcriptomic analysis in both populations indicated that NTBC treatment elicited a broad suppression of genes associated with RNA post-transcriptional modifications, translation, endomembrane system, protein post-translational modifications and protein folding. The CIN population exhibited higher adenosine triphosphate (ATP) production and xenobiotic detoxification. Feeding studies on a mouse model suggest that NTBC could be used as a control method of bed bugs by host treatment. CONCLUSION: The results indicate that NTBC can be used as a new active ingredient for bed bug control by topical or oral treatment and shed light on the molecular mechanisms of suppressed tyrosine metabolism following NTBC treatment. © 2025 Society of Chemical Industry.