Immersed boundary-lattice Boltzmann method was used to study the failure of automobile door sealing strip considering fluid-structure interaction under pressure difference. Based on the actual vehicle model, a two-dimensional calculation model of simplified automobile door sealing strip was established by using immersed boundary method, and practical problems such as the equivalent sealing strip wall thickness correction, wall friction, and pressure balance holes were solved. The accuracy of the model was verified by finite element method. The unsteady pressure outside the vehicle was obtained by CFD and verified by wind tunnel experiment, which could be used as references for setting boundary conditions. In the process of studying the seal failure, by setting the average value, the fluctuation amplitude and the frequency of pressure difference, an automatic iterative program was compiled to obtain the failure situations of the seal under critical pressure difference conditions. The results show that the constant value of the unsteady pressure outside vehicle is the dominant factor, then the coupling between the unsteady pressure frequency and the sealing strip natural frequency, or the increase of the fluctuation range will aggravate seal failure.