Titanium dioxide nanoparticles (TiO₂ NPs) are used extensively in our daily lives, and their toxic effects on the placenta have been reported. Animal studies indicated that placental development is impaired after maternal exposure of TiO₂ NPs, but the underlying mechanisms remain largely unknown. In the present study, we used a human trophoblast-derived cell, HTR8-SVneo, to determine how TiO₂ NPs affected placental functions, and found out potential reversal targets. TEM was employed for TiO₂ NPs morphology observation and uptake assessment. RT-PCR was used to detect the expression of both mRNA and miRNA, and western blotting was used for protein examination. Cell invasion ability was evaluated by Transwell assay, and cytoskeletons were observed by immunofluorescence combined with confocal microscope examination. We found that TiO₂ NPs disrupted cytoskeletons and impaired cell invasion ability. Further investigations showed that TiO₂ NPs increased the expression of a microRNA (miR-96-5p), which targeted and down-regulated the translation of EZR mRNA, a gene that encodes ezrin protein, and affected the cell cytoskeletons and ultimately cell invasion ability. When the expression of miR-96-5p was down-regulated, the expression level of ezrin protein was also reversed, and cell invasion ability was partially restored. Collectively, we determined how miR-96-5p mediates TiO₂ NP-induced placental dysfunction, and provided a potential rescue target for future therapy.