In this study, we propose a molecular engineering strategy that enables the synthesis of partially biodegradable isosorbide-based polycarbonates through a solvent-free melt polycondensation process. By incorporating a small fraction of ethylene oxide–functionalized comonomers into the polymer backbone, melt reactivity and chain-growth efficiency were significantly improved, allowing the formation of high-molecular-weight polycarbonates. The resulting materials simultaneously exhibited high mechanical strength, excellent optical transparency, and elevated thermal resistance, demonstrating that sustainable monomer systems can be successfully translated into high-performance polymer architectures. Notably, standardized aerobic biodegradation confirming partial biodegradability that is absent in conventional aromatic polycarbonates. In addition, cytocompatibility assessments indicated negligible cellular toxicity, supporting the suitability of these materials for applications biological contact. The overall synthetic route showed favorable green chemistry metrics, underscoring both environmental efficiency and scalability.