Introduction: Lead oxide nanoparticles are generated during high-temperature processes at metallurgical plants and emitted in the atmosphere, thus posing high risks of human inhalation exposures. Despite a well-known toxic effect of lead and its nano-sized compounds on the nervous, hematopoietic, urinary, and reproductive systems, data on specific features of an acute inhalation exposure to its nanoparticles are still scarce. Objective: To conduct an experimental study of acute toxicity induced by inhalation exposure to lead oxide nanoparticles in rats. Materials and methods: The experiment was carried out on outbred female rats with the body weight of 247.9 ± 10.5 g divided into two (exposure and control) groups of 10 animals each. A single inhalation exposure to lead oxide nanoparticles (PbO NPs) at the concentration of 0.215 mg/m3 lasted four hours. The nanoparticle shape was spherical with a mean diameter of 18.2 ± 4.2 nm. Blood was taken from the tail vein of the rats to assess its hematologic parameters while the bronchoalveolar lavage fluid (BALF) was obtained to establish its cytological and biochemical characteristics 24 hours after the exposure. Results: After the single inhalation exposure to PbO NPs, the results of the complete blood count showed an increased granulocyte count and a compensatory increase in erythropoiesis manifested by a significant growth of the reticulocyte percentage. The BALF analysis demonstrated that the exposure induced a pronounced cellular reaction in the lower airways accompanied by an increase in the neutrophil count and the neutrophil to alveolar macrophage ratio, which is an indicator of the cytotoxic effect of PbO NPs. Conclusion: Inhalation exposure to PbO NPs at the experimental dose causes both general toxic and cytotoxic effects. The foregoing justifies the necessity of further studies aimed at establishing a no-effect concentration for lead oxide nanoparticles.