The formation and evolution of ionospheric irregularities are closely connected with the instabilities of ionospheric plasma. However, no much consideration of the coupling between upper and lower parts of the ionosphere has ever been taken so far in the study of such instabilities in mid‐ and low‐latitudes. In this paper, a full discussion was presented on the roles played by the existence of both E region Pedersen and Hall conductivity and F region Pedersen conductivity. A complete, common expression of ionospheric plasma gradient‐drift instability under such a coupling was deduced for mid‐ and low‐latitudes based on a three‐layer model developed earlier only for high latitude area. With this model, the observed phenomenon that in some places, the instability occurrence rate is higher in top F region than in the bottom‐side can be explained well. Besides, the model also shows that the evolution of nighttime F region gradient‐drift instability will be slowed down due to the coupling between E and F regions and make the instability growth rate vary with directions in mid‐latitude. It is concluded that the development of gradient‐drift instability in nighttime F region not only depends on the local conditions, but also affected by state of E region that is connected to F region with the same geomagnetic field lines.