The anticancer drug bicalutamide was co-milled with either Macrogol 6000 or Poloxamer 407, and the physicochemical parameters that drive the phase transition of binary systems and influence the dissolution modification of bicalutamide were studied. Milled binary systems with reduced particle size were assessed by scanning electron microscopy and laser diffraction measurements. The results of thermal analysis supported by X-ray diffractometry confirmed the reduction of the crystallinity of bicalutamide co-milled with Macrogol 6000. Infrared spectroscopy was used to determine the molecular structure of the samples and indicated weak interactions between drug and polymer molecules. Two mechanisms were identified and were involved in up to 11-fold enhanced dissolution. The first one was based on improved wettability due to a decreased contact angle in samples containing Macrogol 6000. The second one relied on the solubilization of bicalutamide within nanoaggregates formed by Poloxamer 407 that resulted from its surface activity. This finding was confirmed with fluorescence spectroscopy, dynamic light scattering and cryogenic transmission electron microscopy assays. Given the dissolution rate-limited absorption combined with the reduced bioavailability of bicalutamide as a BCS class II drug, the assessment of the mechanisms driving the increase in drug dissolution is of particular importance in drug development.