Near-epicentral mesopause airglow perturbations, driven by infrasonic acoustic waves (AWs) during a nighttime analog of the 2011 M9.1 Tohoku-Oki earthquake, are simulated through the direct numerical computation of the 3D nonlinear Navier-Stokes equations. Surface dynamics from a forward seismic wave propagation simulation, initialized with a kinematic slip model and performed with the SPECFEM3D_GLOBE model, are used to excite AWs into the atmosphere from ground level. Simulated mesopause airglow perturbations include steep oscillations and persistent nonlinear depletions up to 50% and 70% from the background state, respectively, for the hydroxyl OH(3,1) and oxygen O(1 S) 557.7-nm emissions. Results suggest that AWs excited near a large earthquake's epicenter may be strong enough to drive fluctuations in mesopause airglow, some which may persist after the AWs have passed, that could be readily detectable with ground- and/or satellite-based imagers. Synthetic data demonstrate that future airglow observations may be used for the characterization of earthquake mechanisms and surface seismic waves propagation, potentially complementing tsunami early-warning systems based on total electron content (TEC) observations. Plain Language Summary Large earthquakes can produce substantial Earth's surface deformation. For earthquakes that occur offshore, sea floor deformation may also result in ocean surface displacements that generate tsunamis. At the interface with the atmosphere, these displacements can serve as a source of very low frequency acoustic waves. Reaching the upper atmosphere (∼70 km and higher), these waves can be strong enough to form shock waves and generate observable disturbances. This paper reports the results of numerical simulations of ∼80–90-km altitude airglow disturbances driven by strong acoustic waves excited during a hypothetical nighttime equivalent of the 2011 Tohoku-Oki earthquake (magnitude 9.1). Modeling results show that, for such large earthquakes if occurring at nighttime, airglow disturbances could be readily detected with specialized ground- and space-based imagers. The possibility to detect airglow disturbances earlier than the arrival of the tsunami at the shore points to the potential applicability of such observations for tsunami early-warning systems. Also, the results suggest that such observations can be a useful tool for the characterization of earthquake processes and the propagation of seismic waves.