Achieving consistent liquid thickness in Liquid Phase Transmission Electron Microscopy (LPTEM) is essential for repeatable, high-resolution imaging. Inconsistencies in chip deformation during clamping can lead to variation in liquid layer thickness and compromise imaging quality. This research develops a simulation–experiment framework to evaluate and minimize deformation in MEMS-based liquid cells, with the goal of improving mechanical repeatability during assembly. The modeling approach begins with 2D finite element simulations to identify critical deformation trends, followed by uncertainty quantification (UQ) and geometry optimization to improve chip flatness. These insights guide full 3D simulations, where the lid geometry is refined to reduce chip deformation and maintain a uniform inter-chip gap near the membrane region. The 50 nm SiNx membrane is decoupled from the main model and studied separately using extracted boundary conditions to reduce computational cost. In parallel, white-light interferometry is used to characterize chip curvature at multiple torque levels using a previous-generation holder. A Gauge Repeatability and Reproducibility (R&R) analysis shows that the experimental method reliably distinguishes deformation trends due to torque variation. Simulation and experiment show qualitative agreement in chip bowing behavior supporting optimization strategy. This work delivers a simulation–experiment workflow for improving mechanical repeatability in MEMS-based LPTEM holders, providing a foundation for future design enhancements and fabrication.