Abstract Owing to the limited diversity of structural topologies and pore features, it remains a tremendous challenge to elaborately design and synthesize three‐dimensional covalent organic frameworks (3D COFs) for efficient gas separation. In this study, we present a series of isoreticular 3D COFs using [6 + 4] design strategy based on a designed 6‐coordinated (6‐c) building block with twistable D 3 ‐symmetric configuration and three different rectangular building blocks, named JUC‐320, ‐321, and ‐322, respectively. The torsional flexibility of 6‐c building blocks enables the targeted network to adopt an unprecedented self‐catenated ibd‐r topology with reduced pore sizes. Remarkably, these COFs exhibit exceptional performances in C 3 H 6 /C 2 H 4 separation with high adsorption ratios and selectivities. Dynamic breakthrough experiments further confirmed their ability to efficiently separate C 3 H 6 /C 2 H 4 mixtures (30/70, v/v), yielding polymer‐grade C 2 H 4 (>99.99%). This work offers a useful strategy for constructing 3D COFs with unprecedented topologies and porous architectures toward efficient gas separation.