Since 2005, more than 250 oil spill accidents have occurred in coastal areas and rivers in China, and the risk of oil spill accidents is higher. When oil spill is occurring, it will harm the river water and even normal life of nearby residents. As such, the challenges faced in responding to oil spill of inland river water crossing pipeline merit wider discussion. The Yellow River is a very important river in China and is a high risk area for oil spill due to the leakage of crude oil in across pipeline. Based on the hydrodynamic model, 12 kinds of oil spill scenarios are simulated by MIKE21 OilSpill module, and the influence of wind, water and leakage position on the oil spill drift and diffusion pattern is analyzed. According to the simulation results and the river’s own characteristics, nine Key Sections of Emergency Disposal (KSED) in high-risk waters are obtained, and effective emergency response time of different critical sections which are given to provide technical support for oil spill emergency preparedness work. Results show that the influence of different water phases and leakage location on spill velocity is relatively large. The diffusion velocity of oil spill in flood season is much higher than that in dry season. When leakage point is in the middle position, oil spill velocity is the fastest, followed by the south bank and the North bank. The influence of wind period on the diffusion rate of oil spill is relatively weak, which has a certain effect on the shape of oil spill contaminated zone. When strong wind, flood season and middle position leakage occur, oil spill diffuses fastest with water flow drift, and oil spill emergency disposal is most difficult. According to the need of oil spill emergency preparedness, the easily accessible sluice and bridge structures are selected as the KSED treatment in the length of the river reach studied. The time to reach the KSED of the spillway front is calculated by simulation. Because of the accuracy of the simulation results of this model on key sections of emergency disposal and effective emergency disposal time, Lanzhou Petrochemical Company successfully handled a large-scale oil spill practice. These successful oil spill simulation technology and practice cases about responding to oil spill prove its feasibility. The accuracy of KSED and effective emergency disposal time will be able to provide a new promising responding method to control oil spill pollution.