Burst drug release is often considered a negative phenomenon resulting in unexpected toxicity or tissue irritation. Optimal release of a highly soluble active pharmaceutical ingredient (API) from hypromellose (HPMC) matrices is technologically impossible; therefore, a combination of polymers is required forreduction. Promising variant could be seen in combination of HPMC and insoluble Eudragits as water dispersions. These can be applied only on API/insoluble filler mixture as over-wetting prevention. The main hurdle is a limited water absorption capacity (WAC) of filler. Therefore, the object of this study was to investigate the dissolution behavior of levetiracetam from HPMC/Eudragit NE matrices using magnesium aluminometasilicate (Neusilin US2) as filler with excellent WAC. Part of this study was also to assess influence of thermal treatment on quality parameters of matrices. The use of Neusilin allowed the application of Eudragit dispersion to API/Neusilin mixture in one step during high-shear wet granulation. HPMC was added extragranularly. Obtained matrices were investigated for qualitative characteristics, NMR solid-state spectroscopy (ssNMR), gel layer dynamic parameters, SEM, and principal component analysis (PCA). Decrease in (max. of 33.6%) and dissolution rate, increase in fitting to zero-order kinetics, and paradoxical reduction in gel layer thickness were observed with rising Eudragit NE concentration. The explanation was done by ssNMR, which clearly showed a significant reduction of the API particle size (150–500 nm) in granules as effect of surfactant present in dispersion in dependence on Eudragit NE amount. This change in API particle size resulted in a significantly larger interface between these two entities. Based on ANOVA and PCA, thermal treatment was not revealed as a useful procedure for this system.