Recently, the wedge self-locking nut, a special anti-loosening product, is receiving more attention because of its excellent reliability in preventing loosening failure under vibration conditions. The key characteristic of a wedge self-locking nut is the special wedge ramp at the root of the thread. In this work, the effect of ramp angle on the anti-loosening ability of wedge self-locking nuts was studied systematically based on numerical simulations and experiments. Wedge self-locking nuts with nine ramp angles (10 deg, 15 deg, 20 deg, 25 deg, 30 deg, 35 deg, 40 deg, 45 deg, and 50 deg) were modeled using a finite element (FE) method, and manufactured using commercial production technology. Their anti-loosening abilities under transversal vibration conditions were analyzed based on numerical and experimental results. It was found that there is a threshold value of the initial preload below which the wedge self-locking nuts would lose their anti-loosening ability. This threshold value of initial preload was then proposed for use as a criterion to evaluate the anti-loosening ability of wedge self-locking nuts quantitatively and to determine the optimal ramp angle. Based on this criterion, it was demonstrated, numerically and experimentally, that a 30 deg wedge ramp resulted in the best anti-loosening ability among nine ramp angles studied. The significance of this study is that it provides an effective method to evaluate the anti-loosening ability of wedge self-locking nuts quantitatively, and determined the optimal ramp angle in terms of anti-loosening ability. The proposed method can also be used to optimize other parameters, such as the material properties and other dimensions, to guarantee the best anti-loosening ability of wedge self-locking nuts.