Non-ferrous metallurgical slags (NFM slag) containing heavy metals have been used as supplementary cementitious materials in the cement concrete industry. The NFM slag pozzolanic reaction is highly dependent on the reactivity of the aluminosilicate glass phase, while the effect of heavy metal introduced during high-temperature smelting on the structural feature and dissolution process of aluminosilicate glass in NFM slag remains unclear. In this study, the synthetic CaO-SiO2-Al2O3 glasses based on the chemical compositions of common NFM slag are prepared to investigate the influence of Mn on the glass structure and dissolution activity. The results reveal that the incorporation of Mn into the glass structure was depolymerized by increasing the amount of non-bridging oxygen due to Mn as the network modifier and intermediate in the glass structure. Compared with non-modified glasses, the Mn-modified ones exhibit higher aluminum and silicon ion dissolution rates. The increasing non-bridging oxygen of glass modified by Mn can promote the dissolution-precipitation balance in the early stage. The precipitation layer was observed at approximately 20 nm thickness on the particle’s surface. Furthermore, the addition of Mn reduces the activation energy required for the dissolution of Al and Si, which could be used to indicate the different reactivity under different dissolution temperatures. This study provides dissolution-precipitation insights into the interaction between glass structure and dissolution process in the presence of Mn, contributing to the effective utilization of SCMs containing heavy metals in construction materials.