The substitution of toxic precursors such as bisphenol A by renewable and safer molecules has become a major challenge. To overcome this challenge, the 12 principles of green chemistry should be taken into account in the development of future sustainable chemicals and processes. In this context, this paper reports the highly efficient synthesis of oligo-isosorbide glycidyl ethers from bio-based starting materials by a rapid one-pot heterogeneous ultrasound-assisted synthesis. It was demonstrated that the use of high-power ultrasound in solvent-free conditions with sodium hydroxide microbeads led for the first time to a fully epoxidated prepolymer with excellent epoxy equivalent weight (EEW). The structure of the epoxy precursor was characterized by FT-IR, NMR spectroscopy and high-resolution mass spectrometry (HRMS). The efficiency of the ultrasound-assisted synthesis was attributed to the physical effects caused by micro-jets on the surface of the solid sodium hydroxide microspheres following the asymmetrical collapse of cavitation bubbles.