The development of new applications based on glass doped with nanoparticles is growing in interest during the last years. The structure and properties of Ca-based silicate nanoparticles formed in situ in a silica matrix through a phase separation mechanism were investigated by using Molecular Dynamics simulations and compared to nanoparticles formed from MgO-codoping. We showed that such nanoparticles have non-spherical shape, are amorphous and inhomogeneously distributed in the host glass. In this modeled structure, a release of non-bridging oxygen atoms, due to a depolymerization phenomenon of the nanoparticles’ silica network, was observed. Besides, we demonstrated that nanoparticles’ composition is size-dependent. Compared to Mg-silicate nanoparticles, Ca-based nanoparticles are larger, less concentrated in Ca, and we observed a steeper concentration change during the phase separation process. Those differences are related to the diffusion coefficients of Ca and Mg. This numerical analysis informs on the alkaline-earth nanoparticles’ properties within a host silica glass, which can be a relevant guide for the development of new materials for applications such as nanoparticle-doped optical fibers.