Mechanical properties of the nucleus are remodeled not only by extracellular forces transmitted to the nucleus but also by internal modifications, such as those induced by viral infections. During herpes simplex virus type 1 infection, the viral regulation of essential nuclear functions and growth of the nuclear viral replication compartments are known to reorganize nuclear structures. However, little is known about how this infection-induced nuclear deformation changes nuclear mechanobiology. Our analyses showed that the nucleus softens during the infection. To understand why this happens, we used microscopy and computational methods to study how the mechanical components of the nucleus are modified during the infection. We discovered that the viral replication compartment occupying the nuclear center has a low biomolecular density compared to the centrally located euchromatin in noninfected cells. The nuclear lamina was also modified such that in the infection the amount of lamin proteins increased and the nuclear envelope had more outward curved regions and moved less in infection compared to noninfected cells. The computational modeling of virus-induced changes in cellular forces showed that the most probable cause for the decreasing nuclear stiffness is the removal of lamina-associated domains or the decrease in outward forces, such as reduced intranuclear osmotic pressure and cytoskeletal pull. The simulations showed that an increase in the nuclear envelope tension can occur with a decrease in nuclear stiffness. Based on these findings, we propose a mechanical model that explains mechanistic coordination between the nuclear deformation in infection and decreased nuclear stiffness.