The objective of this study is to examine the effects of wind-driven rain pressure loads on the structural reliability of low-rise buildings under extreme weather conditions. Pressure sensors, rain sensors, and wind measuring devices were installed on the surfaces of representative low-rise building samples. Load characteristics, including load magnitudes, distributions, and variation tendencies, were measured under different wind speeds, directions, and rain intensities over long periods, with correlation analysis carried out for all relevant parameters between loads and meteorological factors. A mechanical modeling framework was developed that takes into account uncertainty associated with wind-driven rain pressure loads, materials, and structural geometries. Failure probabilities and reliability indices were calculated for different critical structural components using reliability theory, with a focus on potential modes of failure and reliability deterioration due to fatigue. Based on the above investigation, optimal design guidelines were proposed, and their feasibility was confirmed by several engineering applications.