Increasing demand for high performance, stable, and affordable sensors for applications in process control industry has led to development of a miniature pressure sensor. This development, made possible by recent advances in microelectromechanical systems (MEMS) fabrication, utilizes polysilicon-sensing technology. The unique polysilicon piezoresistive sensor (PPS) measures differential pressure (DP) based on deformations of a multilayer/multimaterial diaphragm, which is about 2 μm thick. Deformations of a diaphragm, subjected to changes in pressure, are sensed by the piezoresistive bridge elements. Determination of the loading pressures from strains of the piezoresistors is based on computations relying on a number of material specific and process dependent coefficients that, because of their nature, can vary, which may lead to uncertainties in displayed results, especially when temperature changes also. To establish an independent means for measurements of the thermomechanical (TM) deformations of the PPS diaphragms and to validate the coefficients used, a hybrid methodology, based on measurements using optoelectronic laser interferometric microscope (OELIM) and finite element method (FEM) computations coupled with uncertainty analysis provided by unique closed form formulations, was developed. This methodology allows highly accurate and precise measurements of TM deformations of diaphragms, as well as their computational modeling/simulations, and is a basis for “design by analysis” approach to efficient and effective developments of new MEMS sensors. In this paper the hybrid approach is described and its use is illustrated by representative examples addressing high-pressure MEMS sensors.