Equatorial plasma bubbles are common in the low‐latitude ionosphere at night, particularly at solar maximum. The bubbles form on the bottomside of the F‐layer as a result of the Rayleigh‐Taylor instability and then drift upwards and to the east. As the bubbles evolve, the entire north‐south extent of the plasma flux tubes in the bubbles becomes depleted, and the bubbles take the form of vertically elongated wedges of depleted plasma. The east‐west width of a bubble domain can be several thousand kilometers and the plasma density depletion in the bubbles varies from a factor of 10 to 1000. Because equatorial plasma bubbles could have an appreciable effect on the upper atmosphere, a time‐dependent, three‐dimensional, high‐resolution model of the global thermosphere was used to calculate the response of the neutral gas to “idealized” plasma bubble depletions. The model predicts that there are both neutral density and temperature depressions and enhancements in association with the plasma bubbles. The bubble regions can contain either neutral gas enhancements or depressions depending on the background conditions, which change throughout the night. However, the calculated neutral gas perturbations are small, with maximum neutral density perturbations of 6% and maximum temperature perturbations of about 35°K. Nevertheless, these results support the recent experimental evidence that plasma bubbles produce depletions in the neutral density.