Hydrogen as the cleanest energy carrier is a promising alternative renewable resource to fossil fuels. There is an ever-increasing interest in exploring efficient and cost-effective approaches of hydrogen production. Recent experiments have shown that single platinum atom immobilized on the metal vacancies of MXenes allows a high-efficient hydrogen evolution reaction (HER). Here using ab initio calculations, we design a series of substitutional Pt-doped Ti C T (Ti C T -Pt) with different thicknesses and terminations (n = 1, 2 and 3, T = O, F and OH), and investigate the quantum-confinement effect on the HER catalytic performance. Surprisingly, we reveal a strong thickness effect of the MXene layer on the HER performance. Among the various surface-terminated derivatives, TiCF-Pt and TiCHO-Pt are found to be the best HER catalysts with the change of Gibbs free energy ΔG ∼ 0 eV, complying with the thermoneutral condition. The ab initio molecular dynamics simulations reveal that TiCF-Pt and TiCHO-Pt possess a good thermodynamic stability. The present work shows that the HER catalytic activity of the MXene is not solely governed by the local environment of the surface such as Pt single atom. We point out the critical role of thickness control and surface decoration of substrate in achieving a high-performance HER catalytical activity.