In order to study the instability mechanism and prevention measures of subgrade engineering diseases prone to overall slip during the filling process and opening operation period of soft foundation embankment on expressway mountain slope, and to achieve the purpose of quickly and effectively treating subgrade engineering diseases and ensuring engineering safety of subgrade during construction and operation period, taking the overall instability of a typical mountain slope embankment section of an expressway in China as an engineering case, engineering investigation, geological investigation, Geo slope simplified Bishop calculation, FLAC3D numerical simulation, and field settlement and displacement measurement were carried out. The results show that the low shear strength and poor stability of the foundation soil at the embankment section mainly led to the deformation of the subgrade fill at the top of the anti-slide pile at the foot of the slope. Based on the accurate understanding of the mechanism of instability, the corresponding engineering treatment are proposed, that is, on the basis of setting anti-slide piles at the foot of the original embankment slope, adding a certain depth of basement replacement to ensure that the embankment and foundation are prevented from shallow slippage. Then, the safety factors of subgrade slope stability before and after treatment are compared and calculated by Geo-slope software, and the effect of treatment measures is pre-evaluated, the safety factor increases from 0.831 before treatment to 1.452 after treatment, meeting the specification requirements. The FLAC3D software is used to compare and analyze the water level displacement, the settlement of foundation, and roadbed before and after treatment. Compared with before treatment, the horizontal displacement and settlement of foundation and roadbed after treatment are obviously reduced, and the stability is greatly improved. The numerical simulation results are basically consistent with the measured results during in situ testing, which verifies the reliability of treatment measures. According to the specific engineering problems of soft foundation embankment on slope, only when the mechanism of instability is known accurately, then effective treatment measures could be adopted.