[en] When considering f elements, solvent extraction is primarily used for the removal of lanthanides from ore and their recycling, as well as for the separation of actinides from used nuclear fuel. Understanding the complexation mechanism of metal ions with organic extractants, particularly the influence of their molecular structure on complex formation is of fundamental importance. Herein, we report an extraordinary (up to two orders of magnitude) change in the extraction efficiency of f elements with two diastereomers of dimethyl tetraoctyl diglycolamide (Me${}_2$‐TODGA), which only differ in the orientation of a single methyl group. Solvent extraction techniques, extended X‐ray absorption fine structure (EXAFS) measurements, and density functional theory (DFT) based ab initio calculations were used to understand their complex structures and to explain their complexation mechanism. We show that the huge differences observed in extraction selectivity results from a small change in the complexation of nitrate counter‐ions caused by the different orientation of one methyl group in the backbone of the extractant. The obtained results give a significant new insight into metal–ligand complexation mechanisms, which will promote the development of more efficient separation techniques. (© 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim)