Through-glass vias (TGVs) are a foundational technology for glass-based packaging, enabling the realization of advanced three-dimensional (3D) integration platforms. Glass offers superior electrical insulation, mechanical robustness, and intrinsic compatibility with optical signal transmission, making it well-suited for electronic, photonic, and microfluidic applications. However, integrating copper and other materials into glass substrates presents significant reliability challenges, particularly under thermal stress. This study provides a comprehensive modeling and experimental analysis of TGV failure mechanisms, emphasizing the roles of glass composition, via aspect ratio, and feature size. Finite element (FE) simulations identified two dominant failure modes: copper delamination due to inadequate seed layer adhesion and glass cracking driven by stress concentration at via edges. These failures were found to be highly sensitive to the mechanical and thermal properties of the glass and the geometry of the TGVs. Additional material modeling was used to determine the optimal modulus and coefficient of thermal expansion (CTE) for the liner film to ensure compatibility with both copper and glass. The FE model was extended to simulate stress evolution with the liner in place, demonstrating a significant reduction in peak stress and improved structural integrity. Based on insights from the simulation, a multilayer liner film was developed and integrated into the TGV structure. The liner was designed to act as a stress buffer, simultaneously improving adhesion and reducing stress transmission to the glass. Experimental validation through thermal cycling and annealing tests confirmed the liner’s effectiveness in reducing both delamination and glass cracking. We will also discuss integration of these multilayer liners into an optimized process flow for TGV fabrication. In summary, we have developed a modeling framework that provides predictive insights into stress behavior in glass vias and guides material selection and development for reliability improvements. The key innovation of this research lies in establishing a closed-loop methodology that integrates simulation-driven material design, co-optimization of tool and process, and targeted thermal-mechanical testing—enabling a robust framework for solving reliability challenges in TGV structures and accelerating the adoption of glass-based 3D integration technologies. These findings are particularly relevant for glass-based 3D packaging platforms involving microfluidic channels and optical signal transfer, where mechanical robustness and interfacial integrity are critical.