This research focuses on optimizing transition metal nanocatalyst immobilization and activity to enhance ethane dehydrogenation. Ethane dehydrogenation, catalyzed by thermally stable Irn (n = 8, 12, 18) atomic clusters that exhibit a cuboid structure, was studied using the B3LYP method with triple-ζ basis sets. Relativistic effects and dispersion corrections were included in the calculations. In the dehydrogenation reaction Irn + C2H6 → H-Irn-C2H5 → (H)2-Irn-C2H4, the first H-elimination is the rate-limiting step, primarily because the reaction releases sufficient heat to facilitate the second H-elimination. The catalytic activity of the Ir clusters strongly depends on the Ir cluster size and the specific catalytic site. Cubic Ir8 is the least reactive toward H-elimination in ethane: Ir8 + C2H6 → H-Ir8-C2H5 has a large (65 kJ/mol) energy barrier, whereas Ir12 (3 × 2 × 2 cuboid) and Ir18 (3 × 3 × 2 cuboid) lower this energy barrier to 22 and 3 kJ/mol, respectively. The site dependence is as prominent as the size effect. For example, the energy barrier for the Ir18 + C2H6 → H-Ir18-C2H5 reaction is 3, 48, and 71 kJ/mol at the corner, edge, or face-center sites of the Ir18 cuboid, respectively. Energy release due to Ir cluster insertion into an ethane C-H bond facilitates hydrogen migration on the Ir cluster surface, and the second H-elimination of ethane. In an oxygen-rich environment, oxygen molecules may be absorbed on the Ir cluster surface. The oxygen atoms bonded to the Ir cluster surface may slightly increase the energy barrier for H-elimination in ethane. However, the adsorption of oxygen and its reaction with H atoms on the Ir cluster releases sufficient heat to yield an overall thermodynamically favored reaction: Irn + C2H6 + 1/2O2 → Irn + C2H4 + H2O. These results will be useful toward reducing the energy cost of ethane dehydrogenation in industry.