Covalent organic frameworks (COFs) are crystalline porous polymers with designable structures and properties. Their crystallization typically relies on trial- and-error experimentation involving harsh conditions, including organic solvents, presenting significant obstacles for rational design and large-scale production. Herein, we present a liquid crystal-directed synthesis methodology and its implementation for up to gram-scale production of highly crystalline COFs in water and air. It is compatible with monomers of different structures, shape, size, length of side chains, and electron-donating, electron-accepting, and heterocyclic substitutions near reactive sites. Seventeen types of donor–acceptor two-dimensional COFs including four types of new ones and a three-dimensional COF with a yield of up to 94% were demonstrated, showing great generality of the method. The as-synthesized donor–acceptor COFs are organic semiconductors and contain macropores besides intrinsic mesopores which make them attractive catalysts. The production of H₂O₂ under visible light in water was studied and the structure–property relationships were revealed. The production rate reached 4347 μmol h⁻¹ g_cat⁻¹, which is about 467% better than that of the benchmark photocatalyst g-C₃N₄. This study will inspire the mild synthesis and scale-up of a wide spectrum of COFs and organic semiconductors as efficient catalysts, promote their structure–property investigation, and boost their applications.