Nd:glass has become the predominant gain medium for achieving high-energy laser outputs to the order of hundreds of joules, owing to its high energy storage capacity, capacity for large apertures, and excellent optical homogeneity. However, in large-aperture Nd:glass laser amplifiers, surface distortion induced by mechanical clamping is a principal factor degrading laser wavefront quality. To systematically investigate the influence of clamping methods and structural parameters on wavefront distortion, this study employs a combined approach of numerical simulation and experimental validation. The results demonstrate that side-symmetric clamping induces low-frequency wavefront aberrations dominated by first-order astigmatism. The magnitude of these aberrations intensifies with an increased number of clamping screws but is relatively insensitive to variations in screw spacing. In contrast, front-side clamping generates significantly lower wavefront aberrations than side clamping. Further analysis indicates that the clamping-induced wavefront aberration components are predominantly low-frequency, arising primarily from macroscopic surface profile changes. Based on these findings, this paper proposes optimization strategies for clamping force and principles for selecting key structural parameters, thereby providing a theoretical foundation and critical technical support for the low-aberration clamping design of Nd:glass components in high-power laser systems.