Oxide supports with high lattice oxygen lability can stabilize the supported nanoparticles at high temperatures. The lattice oxygen lability of lanthanum hexaaluminates (LHAs) substituted with other metals (such as Mg and Fe) as well as their effects on the thermal stability of supported Ir particles were investigated via CO chemisorption, hydrogen temperature-programmed reduction (H2-TPR), oxygen temperature-programmed desorption (O2-TPD), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), inductively coupled plasma (ICP), and scanning electron microscopy/transmission electron microscopy (SEM/TEM) techniques. The H2-TPR results showed that the lattice oxygen lability of lanthanum iron hexaaluminate (LFA) was much higher than that of lanthanum magnesium hexaaluminate (LMA). This variation could be attributed to the difference in the reducibility of Fe/Mg atoms and their substitution sites in the crystallographic lattice. Under the reductive condition, the H2-TPR presented that the amount of reducible lattice oxygen of LFA supported by metallic Ir decreased significantly, implying the existence of the migration of lattice oxygen and formation of oxygen vacancies, as revealed by O2-TPD and XPS results. After thermal aging at 1200 °C, the amount of residual Ir in LFA was about 4 times that of LMA, as shown in the ICP results. The mean size and dispersion of Ir particles in LFA were better than those in LMA, as revealed by the SEM/TEM results, showing the superior thermal stability of the Ir particles in LFA support. Hence, this study concludes that the lattice oxygen lability plays an important role in improving the thermal stability of the Ir@LHAs at high temperatures. Based on characterization results, a model was proposed to explain the interaction between Ir and LHAs and its effect on the thermal stability of the Ir particles.