The development of three-dimensional (3D) covalent organic frameworks (COFs) with large pores and high surface areas is of great importance for various applications. However, it remains a major challenge due to the frequent structural interpenetration and pore collapse after the removal of guest species situated in the pores. Herein, we report for the first time a series of 3D mesoporous COFs through a general method of steric hindrance engineering. By placing methoxy and methyl groups strategically on the monomers, we can obtain non-interpenetrated 3D COFs of diamondoid structures with permanent mesopores (up to 26.5 Å) and high surface areas (>3000 m2 g-1), which are far superior to those of reported conventional COFs with the same topology. This work thus opens a new avenue to create 3D large-pore COFs for potential applications in adsorption and separation of large inorganic, organic, and biological molecules.