In this work, we characterized the electronic structure of CdSe quantum dots embedded in a series of x Na2O, (1–x) SiO2 glass matrices (x = 0, 0.25, 0.33, and 0.5). We analyzed the impact of the glass matrix composition on both the atomic structure of the quantum dot (QD) and the QD/glass interface, as well as the luminescence mechanisms, using density functional theory calculations. The increase of Na2O content in the glass matrices was found to promote the formation of Cd–O and Se–Na interfacial bonds and disrupt the Cd–Se bonds network. In particular, we show that the glass composition directly affects the nature of the highest occupied molecular orbitals (HOMO). According to the atomic structure, band gap distribution, and density of states calculation, we find that there is significant reconstruction of the QD and that the picture sometimes proposed of a “pristine quantum dot” surrounded by glass is not realistic. The introduction of CdSe QD significantly decreased the HOMO–LUMO gap of the glass compared to pristine glasses, and the interfacial bonds greatly contributed to the frontier orbitals without forming midgap states. We propose a new energy diagram, quite different from the traditional model, to explain the luminescence of CdSe quantum-dot-doped glasses, originating from the intrinsic emission of this hybrid system {QD + glass}. These results improve our understanding of the luminescence of CdSe quantum-dot-doped glasses, explaining the reason for the poor quantum efficiency and broad emission linewidth compared with their colloidal counterparts.