Ensuring the long-term, efficient, and safe operation of reservoir dams relies on the slope stability of embankment dams. Periodic fluctuations of the reservoir water level due to reservoir scheduling operations make the slope of the reservoir bank vulnerable to instability. To investigate the influence of various factors and their interactions with embankment dam slope stability under changing reservoir water levels, a global sensitivity analysis method is proposed that accounts for seepage–stress coupling. An embankment dam in Shaanxi Province, China, is studied as an example, with COMSOL Multiphysics software simulating the seepage and slope stability of the dam under fluctuating reservoir water level conditions and seepage–stress coupling. The global sensitivity analysis of factors affecting dam slope stability is accomplished by combining Plackett–Burman and Box–Behnken experimental designs, with ANOVA determining the sensitivity of each factor and interaction term. The results demonstrate that during the impoundment period of the reservoir, the saturation line is concave, and the overall stability safety of the dam slope increases first and then tends to be stable, according to the coefficient. The internal friction angle φ, cohesion c, and soil density ρs represent the three most sensitive factors affecting the stability and safety of the dam slope, while c × ρs is a second-order interaction term with significant sensitivity to the stability and safety coefficient of the dam slope. The reservoir drainage period infiltration line is convex, and dam slope stability first reduced and then increased. The magnitude of water level change H, internal friction angle φ, cohesion c, and soil density ρs are the four most sensitive factors for the coefficient of safety of dam slope stability, while c × ρs, H × ρs, and φ × ρs are the second-order interaction terms with significant sensitivity to the coefficient of safety of dam slope stability. These research findings and methods can offer valuable technical support and reference for the investigation and evaluation of the stability of embankment dam slopes.