The multinucleation effect of silica nanoparticles (SiNPs) had been determined in our previous studies, but the relative mechanisms of multinucleation and how the multinucleated cells are generated were still not clear. This extensional study was conducted to investigate the mechanisms underlying the formation of multinucleated cells after SiNPs exposure. We first investigated cellular multinucleation, then performed time-lapse confocal imaging to certify whether the multinucleated cells resulted from cell fusion or abnormal cell division. Our results confirmed for the first time that there are three patterns contributing to the SiNPs-induced multinucleation in HepG2 cells: cell fusion, karyokinesis without cytokinesis, and cytokinesis followed by fusion. The chromosomal passenger complex (CPC) deficiency and cell cycle arrest in G1/S and G2/M checkpoints may be responsible for the cell aberrant cytokinesis. The activated MAPK/ERK1/2 signaling and decreased mitosis related proteins might be the underlying mechanism of cell cycle arrest and thus multinucleation. In summary, we confirmed the hypothesis that aberrant cytokinesis and cell fusion resulted in multinucleation in HepG2 cells after SiNPs exposure. Since cell fusion and multinucleation were involved in genetic instability and tumor development, this study suggests the potential ability of SiNPs to induce cellular genetic instability. These findings raise concerns with regard to human health hazards and environmental risks with SiNPs exposure.