Hydramethylnon (HM) is a household-use insecticide whose inhalation hazard remains poorly characterized. We combined whole-body disposition analysis with mechanistic assessment in pulmonary and hepatic systems. Structurally identical 18F-labeled HM enabled dynamic positron emission tomography/computed tomography after intratracheal instillation in mice. Pulmonary clearance was rapid, with predominant redistribution to the liver and a fourfold longer half-life for the polyethylene glycol (PEG)-based than the ethanol-based dispersion (26.92 versus 6.59 min). In an air–liquid interface model, HM was cytotoxic to Calu-3 and H441 epithelial cells, whereas barrier-related responses reflected both PEG and HM in Calu-3 cells but predominantly HM in H441 cells. In HepG2 hepatocytes, differentiated THP-1 macrophages, and primary alveolar macrophages, HM induced apoptosis, adenosine triphosphate depletion, mitochondrial loss, impaired respiration, and reactive oxygen species generation without altering glycolysis. In vivo, hepatic apoptosis increased after both three-dose intratracheal instillation and 28-day repeated pharyngeal aspiration, whereas reduced hepatic mitochondrial content and elevated serum transaminases emerged only after 28 days, indicating duration- and cumulative dose-dependent hepatic responses. This study identifies the liver as the principal secondary exposure compartment after respiratory delivery of HM and shows that formulation modifies pulmonary retention, providing route-specific disposition data for hazard identification rather than quantitative risk assessment.