Seawater desalination is gaining interest as global water scarcity looms. Conventional materials limit the improvement of desalination components such as membranes, electrodes, and solar absorbers. The breakthrough in molecular design achieved by covalent organic frameworks (COFs) can potentially lead to developing highly efficient desalination materials. This review presents desalination technologies that have been explored using COFs. Here, after an introduction to the properties of COFs, each desalination technology is comprehensively surveyed, including the process, salt removal mechanism, conventional materials, and technological challenges. The molecular design strategies of COFs are then discussed, highlighting their potential to optimize desalination performance. The advances in COFs’ molecular design for desalination in each technology are then reviewed. The conclusion highlights the key research and development gaps that could be addressed with COFs. This review is a guide to investing in the power of molecular design to address industrial challenges in one of the most important applications, desalination.