Cellulose nanofibers (CNFs) have interesting physicochemical and colloidal properties that have been recently exploited in novel drug delivery systems for tailored release of poorly soluble drugs. The morphology and release kinetics of such drug-delivery systems heavily relied on the drug CNF interactions; however, in-depth understanding of the interactions was lacking. Herein, the interactions between a poorly soluble model drug molecule, furosemide, and cationic cellulose nanofibers with two different degrees of substitution are studied by sorption experiments, Fourier transform infrared spectroscopy, and molecular dynamics (MD) simulation. Both MD simulations and experimental results confirmed the spontaneous sorption of drug onto CNF. Simulations further showed that adsorption occurred by the flat aryl ring of furosemide. The spontaneous sorption was commensurate with large entropy gains as a result of release of surface-bound water. Association between furosemide molecules furthermore enabled surface precipitation as indicated by both simulations and experiments. Finally, sorption was also found not to be driven by charge neutralization, between positive CNF surface charges and the furosemide negative charge, so that surface area is the single most important parameter determining the amount of sorbed drug. An optimized CNF furosemide drug-delivery vehicle thus needs to have a maximized specific surface area irrespective of the surface charge with which it is achieved. The findings also provide important insights into the design principles of CNF-based filters suitable for removal of poorly soluble drugs from wastewater.