The low aqueous solubility of most hydrophobic medications limits their oral absorption. An approach to solve this problem is to make a drug-polymer association. Herein, we investigated the association between rafoxanide (RAF), a surface-active, poorly water-soluble drug, with a commercial hydrophilic polymer povidone. We found that the association is a function of medium composition and could only take place in polar media, such as water. The association is favored by the hydrogen-bond formation between the amide group in RAF and the carbonyl group in povidone. In addition, the association is also favored by the self-association of RAF through π-π interaction between the benzene rings in adjacent RAF molecules. Two-dimensional nuclear magnetic resonance has been applied to investigate the interactions and has confirmed our hypotheses. Geometry optimization confirmed that RAF exists primarily in the antiparallel configuration in the RAF aggregates. This study provides critical information for designing suitable drug-vehicle complexes and engineering the interactions between them to maximize the oral absorption. Our results shed light on drug design and delivery, drug molecule structure-functionality relationship, as well as efficacy enhancement toward interaction engineering.