Myopia is very prevalent worldwide, especially among Asian populations. Orthokeratology is a proven intervention to reduce myopia progression. The current study investigated association between baseline corneal biomechanics and orthokeratology responses, and changes of corneal biomechanics from long-term orthokeratology. We fitted 59 adult subjects having myopia between -4.00D to -5.00D with overnight orthokeratology. Corneal biomechanics was measured through dynamic bidirectional corneal applanation (in terms of corneal hysteresis, CH and corneal resistance factor, CRF) and corneal indentation (in terms of corneal stiffness, S and tangent modulus, E). Subjects with poor orthokeratology responses had lower E (mean 0.474 MPa) than subjects with good orthokeratology responses (mean 0.536 MPa). Successful orthokeratology for 6 months resulted in reducing CH (reduced by 5.8%) and CRF (reduced by 8.7%). Corneal stiffness was stable, but E showed an increasing trend. Among subjects with successful orthokeratology, a higher baseline S resulted in greater myopia reduction (Pearson correlation coefficient, r = 0.381, p = 0.02).