Horizontal wells are more likely than vertical wells to have enlarged wellbore sections due to borehole instability. However, there is scarce research on borehole cleaning of horizontal wells with enlarged wellbore sections. In this paper, we establish a horizontal wellbore model with a breakout enlargement section using field borehole diameter data. We used the three-dimensional computational fluid dynamics (CFD) method and the Realizable k-ε turbulence model with the Euler–Euler approach to simulate the effects of the drilling fluid circulation return speed and the spinning speed of the drill pipe on the cutting movement of conventional horizontal wells and horizontal wells with a breakout enlargement section. The simulation results demonstrate that increasing the drilling fluid circulation return speed and the spinning speed of the drill pipe does not significantly improve the hole cleaning impact for horizontal wells with a breakout enlargement section. We analyzed the effects of the enlargement ratio, ellipticity, and principal axis orientation on the borehole cleaning effect of horizontal wells with a breakout enlargement section. The results show that the cleaning impact is better when the enlargement ratio is lower; moreover, the ellipticity is larger and the principal axis orientation is perpendicular to the gravity direction. This paper fills a gap in the existing theory of hole cleaning in horizontal wells and provides a theoretical basis for improving the hole cleaning effect in actual drilling processes.