Hydroelectric power generation is an important clean energy source, and the stability of water turbine operation determines the quality of hydro energy utilization. For hydro turbines, the layout direction of the draft tube is often only considered from a structural perspective, ignoring the hydrodynamic characteristics. This study adopts the computational fluid dynamics method and verifies the effectiveness of numerical simulation with experimental results, analyzing the influence of asymmetric draft tube layout direction on pressure pulsation of mixed flow turbine. The results show that under different working conditions, there is basically no difference in efficiency corresponding to different inclined directions of the draft tube, and the relative difference in performance values is less than 1%. From the perspective of internal flow, the working condition has a greater impact on the flow, and the draft tube tilt has a smaller impact. Under strong swirling flow conditions in the draft tube, the variational mode decomposition of pressure fluctuation is carried out. Research has found 7 characteristic frequency bands including 140 Hz, 80–90 Hz, 40–46 Hz, 5.5–6.5 Hz, 2.5–3 Hz, 1.67 Hz, and <1 Hz. The frequency of the dominant mode corresponding to the left tilt is higher, while the amplitude of the runner frequency is slightly lower. In general, left tilt is not only more suitable for unit layout but also has a better effect on draft tube pressure fluctuation, which is worthy of application in engineering.