Nuclear mechanics is remodeled not only by extracellular forces but also by internal modifications, such as those induced by viral infections. During herpes simplex virus type 1 infection, the nuclear structures undergo drastic reorganization, but little is known about how nuclear mechanobiology changes as a result. We show that the nucleus softens dramatically during the infection. To understand the phenomenon, we used advanced microscopy and computational modeling. We discovered that the enlarged viral replication compartment had a low biomolecular density, partially explaining the observed nuclear softening. The mobility of the nuclear lamina decreased, suggesting increased rigidity and inability to cause the softening. Computational modeling supported this by showing that decreased outward forces, such as intranuclear osmotic pressure and cytoskeletal pull, explain the decreased nuclear stiffness. Our findings reveal the mechanistic coordination between the infection-induced nuclear deformation and decreased nuclear stiffness.