Static or dynamic elastomeric O-ring seals are installed between joining parts, and play key roles of high pressure-tightening. Sealing performance and structural safety of the O-ring are dependent on groove design, plain diameter, squeeze and applications such as pressure and temperature. In this study, to solve O-ring problem squeezed and highly pressurized under laterally one-sided constrained condition, hyperelastic FE analyses are performed, and FE results are compared with measured ones by computer-aided tomography, deformed shape and extrusion depth of the O-ring. Through the comparisons, FE analysis technique was verified. In order to evaluate design sensitivity, Taguchi method was used to select FE analysis cases. Adjustment parameters are clearance gap, groove comer radius, plain diameter and squeeze. By means of verified FE analysis technique, it has been analysed how the parameters have effects on contact stress fields, internal stress fields, and extrusion depths. Sealing performance has been evaluated based on contact stress fields and contact widths, and structural safety on internal stress and strain, extrusion lengths.