We report the first results of a global ionosphere/thermosphere simulation study that self‐consistently generates large‐scale equatorial spread F (ESF) plasma bubbles in the postsunset ionosphere. The coupled model comprises the ionospheric code SAMI3 and the atmosphere/thermosphere code WACCM‐X. Two cases are modeled for different seasons and geophysical conditions: the March case (low solar activity: F10.7 = 70) and the July case (high solar activity: F10.7 = 170). We find that equatorial plasma bubbles formed and penetrated into the topside F layer for the March case but not the July case. For the March case, a series of bubbles formed in the Atlantic sector with irregularity spacings in the range 400–1,200 km, rose to over 800 km, and persisted until after midnight. These results are consistent with recent GOLD observations. Calculation of the generalized Rayleigh‐Taylor instability (GRTI) growth rate shows that the e‐folding time was shorter for the March case than the July case. Key Points The first results from a high‐resolution, global simulation of equatorial spread F using realistic thermospheric conditions The development of equatorial plasma bubbles is both longitudinally and seasonally dependent Atmospheric waves play an essential role in “seeding” the generalized Rayleigh‐Taylor instability responsible for the instability