Cobalt monoxide (CoO) and lanthanum oxide (La₂O₃) nanoparticles are 2 metal oxide nanoparticles with different redox potentials according to their semiconductor properties. By utilizing these two nanoparticles, this study sought to determine how metal oxide nanoparticle’s mode of toxicological action is related to their physio-chemical properties in human small airway epithelial cells (SAEC). We investigated cellular toxicity, production of superoxide radicals and alterations in gene expression related to oxidative stress, and cellular death at 6 and 24 h following exposure to CoO and La₂O₃ (administered doses: 0, 5, 25, and 50 µg/ml) nanoparticles. CoO nanoparticles induced gene expression related to oxidative stress at 6 h. After characterizing the nanoparticles, transmission electron microscope analysis showed SAEC engulfed CoO and La₂O₃ nanoparticles. CoO nanoparticles were toxic after 6 and 24 h of exposure to 25.0 and 50.0 µg/ml administered doses, whereas, La₂O₃ nanoparticles were toxic only after 24 h using the same administered doses. Based upon the Volumetric Centrifugation Method in vivo Sedimentation, Diffusion, and Dosimetry, the dose of CoO and La₂O₃ nanoparticles delivered at 6 and 24 h were determined to be: CoO: 1.25, 6.25, and 12.5 µg/ml; La₂O₃: 5, 25, and 50 µg/ml and CoO: 4, 20, and 40 µg/ml; and La₂O₃: 5, 25, 50 µg/ml, respectively. CoO nanoparticles produced more superoxide radicals and caused greater stimulation of total tyrosine and threonine phosphorylation at both 6 and 24 h when compared with La₂O₃ nanoparticles. Taken together, these data provide evidence that different toxicological modes of action were involved in CoO and La₂O₃ metal oxide nanoparticle-induced cellular toxicity.