The separation of adjacent lanthanides continues to be a challenge worldwide because of the similar physical and chemical properties of these elements and a necessity to advance the use of clean-energy applications. Herein, a systematic structure-performance relationship approach toward understanding the effect of N-alkyl group characteristics in diglycolamides (DGAs) on the separation of lanthanides(III) from a hydrochloric acid medium is presented. In addition to the three most extensively studied DGA complexants [N,N,N',N'-tetra(n-octyl)-diglycolamide, TODGA; N,N,N',N'-tetra(2-ethylhexyl)-diglycolamide, TEHDGA; N,N'-dimethyl-N,N'-di(n-octyl)-diglycolamide, DMDODGA], 12 new extracting agents with varying substitution patterns were designed to study the interplay of steric and electronic effects that control rare-earth element extraction. Subtle changes in the structure around diglycolamide carbonyl oxygen atoms result in dramatic shifts in the lanthanide extraction strength and selectivity. The effects of the chain length and branching position of N-alkyl substituents in DGAs are elaborated on with the use of experimental, computational, and solution-structure characterization techniques.