Despite intensive investigations, nanoparticle-induced cellular damage is an important problem that has not been fully elucidated yet. Here, we report that silica nanoparticles (SiNPs) demonstrated anticancer influence on glioblastoma cells by the induction of apoptosis or necrosis. These effects are highly cell type-specific, as well as dependent on the size and dose of applied nanoparticles. Exposure of LN-18 and LBC3 cells to different sizes of SiNPs—7 nm, 5–15 nm, or 10–20 nm—at dosages, ranging from 12.5 to 1000 µg/mL, for 24 and 48 h reduced the viability of these cells. Treatment of LN-18 and LBC3 cells with 7 nm or 10–20 nm SiNPs at doses ≥50 µg/mL caused a strong induction of apoptosis, which is connected with an increase of intracellular reactive oxygen species (ROS) production. The 5–15 nm SiNPs exhibited distinct behavior comparing to silica nanoparticles of other studied sizes. In contrast to LBC3, in LN-18 cells exposed to 5–15 nm SiNPs we did not observe any effect on apoptosis. These nanoparticles exerted only strong necrosis, which was connected with a reduction in ROS generation. This suggests that SiNPs can trigger different cellular/molecular effects, depending on the exposure conditions, the size and dose of nanoparticles, and cell type of glioblastoma.