Embryonic genome activation (EGA) marks the transition from dependence on maternal transcripts to an embryonic transcriptional program. The precise temporal regulation of gene expression, specifically the silencing of the Dux/MERVL program during late 2-cell interphase, is crucial for developmental progression in mouse embryos. How this finely tuned regulation is achieved within this specific window is poorly understood. Here, using particle-tracking microrheology throughout the mouse oocyte-to-embryo transition, we identify a surge in cytoplasmic viscosity specific to late 2-cell interphase brought about by high microtubule and endomembrane density. Importantly, preventing the rise in 2-cell viscosity severely impaired nuclear reorganisation resulting in a persistently open chromatin configuration and failure to silence Dux/MERVL. This in turn derailed embryo development beyond the 2- and 4-cell stages. Our findings reveal a mechanical role for the cytoplasm in regulating Dux/MERVL repression via nuclear remodelling during a temporally confined period in late 2-cell interphase.