Rafoxanide (RAF) is a poorly water-soluble drug that forms a complex with povidone K25 (PVP) in a cosolvent system containing acetone and an alk. aqueous medium. This study aims to investigate the impact of RAF-PVP complexation on in vitro and in vivo release of RAF. We prepared two RAF amorphous solid dispersions (ASDs) spray-dried from these two cosolvents. The first is a complexation-based spray-drying using a 70% 0.1 N NaOH solution with 30% acetone. The second is a traditional spray-dried formulation containing 80% acetone and 20% ethanol. Evidence from multiple solid-state characterization techniques indicated that ASDs spray-dried using both methods were amorphous. However, RAF ASDs based on drug-polymer complexation in the feed solution demonstrated not only faster drug release during dissolution testing but also higher in vivo absorption in an animal model. The improved RAF release in the complexation-based ASD is due to (1) high energy state of RAF owing to the amorphous form, (2) high pH in the microenvironment due to the ionized state of RAF and residual sodium hydroxide, (3) increased apparent solubility of RAF results from RAF-PVP complexation in dissolution media and biol. media, and (4) improved wettability.