Covalent organic frameworks (COFs), with their modular architectures and tunable functionalities, provide a versatile platform to design sorbents for the direct capture of CO from air. Here, we combined density functional theory, molecular dynamics, and grand canonical Monte Carlo simulations with experiment to understand structural factors for furthering COF-999-NH's performance as the precursor to COF-999 for direct air CO capture. Small energy differences among laterally shifted stackings suggest intrinsic stacking heterogeneity. The simulations show pronounced layer buckling coupled to extensive amine-nitrile hydrogen bonding and persistent pore water, which initiates undesired polymerization and undermines uptake. The predicted presence of water is confirmed by subsequent experiments. These insights point to a single, actionable design rule: exclude retained water by introducing hydrophobic pore environments to maximize the CO capture efficiency.