This work investigates the interactions of a series of 11 anions with caffeine by utilizing 13C and 1H NMR and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. The aim of this study is to elucidate the molecular mechanisms of ion interactions with caffeine and to study how these interactions affect caffeine aggregation in aqueous solution. The chemical shift changes of caffeine 13C and 1H in the presence of salts provide a measure for anions' salting-out/salting-in abilities on individual carbon and hydrogen atoms in caffeine. The relative influences of anions on the chemical shift of individual atoms in the caffeine molecule are quantified. It is observed that strongly hydrated anions are excluded from the carbons on the six-member ring in caffeine and promote caffeine aggregation. On the other hand, weakly hydrated anions decrease caffeine aggregation by accumulating around the periphery of the caffeine molecule and binding to the ring structure. The ATR-FTIR results demonstrate that strongly hydrated anions desolvate the caffeine molecule and increase aggregation, while weakly hydrated anions have the opposite effects and salt caffeine into solution.