The facile synthesis of yolk-shell-structured nanoparticles (YSNPs) with mobile active metal cores and mesoporous inorganic-organic hybrid silica shells (mHSiO2) is important for their applications. In this work, Pd@mHSiO2 YSNPs have been synthesized in aqueous solution at 95 °C by a one-pot method without the need for extensive purification and separation steps. The method is simple and facile, and ingeniously combines the controlled synthesis of Pd nanocubes, coating of mesoporous silica, and transition from core-shell-structured nanoparticles (CSNPs) to YSNPs. 29Si NMR spectroscopy, FTIR spectroscopy, and detailed control experiments have demonstrated that the incorporation of 1,2-bis(trimethoxysilyl)ethane (BTME) modifies the degree of condensation between the outer hybrid silica layer and the inner pure silica section, and that high temperature water is really responsible for dissolving the inner pure silica layer leading to a transition from the CSNPs to the YSNPs. The obtained Pd@mHSiO2 YSNPs have a controllable diameter, tunable shell thickness, a high specific surface area, and uniform mesoporosity. Thermal stability tests have indicated that the Pd@mHSiO2 YSNPs are remarkably stable at high temperatures up to 650 °C. Importantly, the Pd@mHSiO2 YSNPs exhibit a much higher catalytic activity and hydrothermal stability than Pd@mSiO2 CSNPs or Pd/mHSiO2 NSs in the conversion of levulinic acid (LA) into γ-valerolactone (GVL), because the hollow voids provide low mass-transfer resistance and improve the accessibility of the catalytic sites, and the incorporation of organic groups enhances the hydrothermal stability of the outer shell.