Due to their diverse and tunable composition, distorted lattice and excellent stability, high-entropy ceramics (HECs) hold great promise for catalysis, especially when they present as nanoparticles (NPs). However, current HECs are typically limited to bulky materials with none or fewer defects, because high synthetic temperature (e.g., 1,000–1,200 °C) is usually required to highlight the entropic contribution (TΔS) in ΔG = ΔH − TΔS. Being different with previous strategies, a negative Gibbs free energy for HECs crystallization is obtained by dramatically decreasing the mixing enthalpy (ΔH). Guided by this principle, single-phase high-entropy La(Ni_0.2Mn_0.2Cu_0.2Fe_0.2Co_0.2)O_3−δ perovskite (HE-LMO) NPs were prepared at a relatively low temperature (≤ 500 °C). Interestingly, abundant oxygen vacancies were directly created within HE-LMO NPs, which exhibited good activity in catalytic oxidation. Meanwhile, the high-entropy structure endows as-made HE-LMO with robust stability even with 5 vol.% water in feeding gas. Density functional theory (DFT) calculations revealed that the defective sites in HE-LMO NPs facilitated the charge transfer from HE-LMO to CO, thus activating the adsorbed CO gas. The current work may inspire future design and synthesis of HECs NPs.