Activity models based on the ion and molecule coexistence theory have been widely used in the refining of metallurgical slags, with the SiO2 content of slag playing a crucial role in improving the mechanical properties of refining slag-based cementitious materials. In order to improve the reactivity of SiO2 in slag, this study established a SiO2 activity prediction model for the CaO-Al2O3-SiO2-MgO quaternary slag system based on the ion and molecule coexistence theory, validating the prediction results using reference values from the literature. Following this, the effects of w(SiO2), w(CaO), w(CaO)/w(Al2O3) and R(w(CaO)/w(SiO2)) on SiO2 activity, were explored (where w and R represent content and alkalinity, respectively). The results show that the model could accurately predict the SiO2 activity of refining slag. When the SiO2 content was increased from 10–30%, with 60% w(CaO) and a w(MgO)/w(Al2O3) ratio of 0.25, the SiO2 activity exhibited a trend of initially increasing and then decreasing, with a maximum activity value of 0.1359 reached at 17.5% w(SiO2). When slag contained 15% w(SiO2) and a w(MgO)/w(Al2O3) ratio of 0.25, the SiO2 activity decreased with increasing CaO content, reaching a maximum activity value of 0.1268 when 55% w(CaO) was present. Therefore, by controlling the ratio of w(CaO)/w(Al2O3) and w(CaO)/w(SiO2) in the slag to maintain a ratio of 3, the activity of SiO2 can be effectively increased.