<p>Sand liquefaction is a critical earthquake-induced hazard, and desaturation has been increasingly recognized as a promising countermeasure. To clarify the underlying mechanisms of liquefaction in quasi-saturated sand under cyclic loading, this study employs Discrete Element Method (DEM) simulations, incorporating the compressibility of gas–water mixtures to investigate the liquefaction behavior of quasi-saturated sand. Simulations were conducted under varying confining pressures, relative densities, cyclic stress ratios (CSR), and degrees of saturation, enabling a systematic analysis of macroscopic behavior, microstructural evolution, and energy dissipation. The results demonstrate that desaturation substantially delays the liquefaction triggering and enhances structural stability, with the most pronounced benefits under low CSR. The improvement effect strengthens with confining pressure and density up to an optimum, but decreases thereafter, indicating that desaturation is most effective in shallow to intermediate deposits. At the microscale, the mechanical coordination number and skeletal void ratio effectively capture structural instability and phase transformation processes. Energy dissipation exhibits a staged transition from shear-driven to collision-dominated mechanisms, accompanied by a characteristic phase reversal. The compliance index is introduced to quantify energy–deformation adaptability, showing a rise–peak–fall trend with energy input; its peak is significantly higher under desaturation, reflecting enhanced structural compliance and resistance. These findings provide new insights into the multi-scale mechanisms of liquefaction in quasi-saturated soils and establish a practical quantitative basis for desaturation-based mitigation strategies.</p>