Orthokeratology (OK) is becoming a mainstream modality for myopia correction and control, but its underlying mechanism is not yet fully understood. In this study, the biomechanical response of cornea under the OK lens was investigated to further understand the mechanism of OK therapy. Numerical models of the cornea and OK lens with different corneal refractive powers and myopia degrees were established to analyze features and differences of the spatial displacement and stress distribution in different areas of the anterior corneal surface by finite element method. Displacement distributions on the anterior cornea surface with refractive powers of 39.5, 43, 46 D, and myopia degrees of -1.0, -3.0, -6.0 D demonstrate similar deformation trends and nearly rotationally symmetrical attributes of different corneal parameters. Displacement of mid-peripheral cornea was significantly high compared with that of the central and peripheral cornea, peaking at ~2.4 mm off the corneal apex. The stress increased with the increase in myopia degrees and was significantly large for the myopia degrees of -6.0 D at S1; the stress at S2 and S6 was low and stable and did not differ much at S3; the stress at S4 and S5, however, was extremely high. In summary, simulation result of orthokeratology can effectively evaluate the performance of OK lens and it properly associates with the differential map of the corneal topography. The base curve of the OK lens may also play a role in mid-peripheral corneal steepening. The design around the OK lens’ alignment curve needs to be optimized.© 2023 John Wiley & Sons, Ltd.