AbstractLithium is a metal in increasingly high demand due to its use in lithium-ion batteries. However, the extraction from aqueous resources as brines and seawater, which account for a major percentage of worldwide Li+ reserves, is challenging due to the presence of other interfering metal ions. Crown ethers (CEs) are known to complex metal cations very effectively, but a fundamental understanding of their potential in lithium extraction is still lacking. Therefore, the selective complexation of Li+ over other alkaline (Na+, K+) and alkaline earth metal (Mg2+, Ca2+) ions is investigated by density functional theory (DFT) calculations for 15–, 12–, and 9–membered CEs and their derivatives containing in part nitrogen and sulfur instead of oxygen atoms. Structure optimizations of these CEs are performed in vacuum, and complex stabilities are discussed by evaluating the cavity size, the distances between donor atoms and metal ion, and by performing Hirshfeld charge and Natural Bond Orbital analyses. The qualitative trends obtained from these methods are in good agreement with the complex stabilities, which suggests that they can be used to make simplified predictions of complex stabilities. The selectivity for Li+ compared to Mg2+ in vacuum can be strongly influenced by the ring size, which was the best for B15C5. The general accuracy of DFT is validated by comparing calculations in a polarizable continuum model with the results of a liquid–liquid extraction in a water/dichloromethane mixture using the exemplary extraction of Li+, Na+, K+, Mg2+, and Ca2+ by aza–15–crown–5. By doing so, the DFT trends are confirmed (with the stability of the Mg2+ complex being overestimated while all others are underestimated), suggesting that DFT is a valuable tool for optimizing CE structures to selectively complex Li+ or other metal ions. In the context of increasing global lithium demand, the results of this study can serve the further development of selective and sustainable lithium extraction from the largely unexploited resource of seawater.