Amphotericin B (AmB) and Nystatin (Nys) are the drugs of choice for treatment of systemic and superficial mycotic infections, respectively, with their full clinical potential unrealized due to the lack of high therapeutic index formulations for their solubilized delivery. In the present study, using a coarse-grained (CG) molecular dynamics (MD) simulation approach, we investigated the interaction of AmB and Nys with Polysorbate 80 (P80) to gain insight into the behavior of these polyene antibiotics (PAs) in nanomicellar solution and derive potential implications for their formulation development. While the encapsulation process was predominantly governed by hydrophobic forces, the dynamics, hydration, localization, orientation, and solvation of PAs in the micelle were largely controlled by hydrophilic interactions. Simulation results rationalized the experimentally observed capability of P80 in solubilizing PAs by indicating (i) the dominant kinetics of drugs encapsulation over self-association; (ii) significantly lower hydration of the drugs at encapsulated state compared with aggregated state; (iii) monomeric solubilization of the drugs; (iv) contribution of drug-micelle interactions to the solubilization; (v) suppressed diffusivity of the encapsulated drugs; (vi) high loading capacity of the micelle; and (vii) the structural robustness of the micelle against drug loading. Supported from the experimental data, our simulations determined the preferred location of PAs to be the core-shell interface at the relatively shallow depth of 75% of micelle radius. Deeper penetration of PAs was impeded by the synergistic effects of (i) limited diffusion of water; and (ii) perpendicular orientation of these drug molecules with respect to the micelle radius. PAs were solvated almost exclusively in the aqueous poly-oxyethylene (POE) medium due to the distance-related lack of interaction with the core, explaining the documented insensitivity of Nys solubilization to drug-core compatibility in detergent micelles. Based on the obtained results, the dearth of water at interior sites of micelle and the large lateral occupation space of PAs lead to shallow insertion, broad radial distribution, and lack of core interactions of the amphiphilic drugs. Hence, controlled promotion of micelle permeability and optimization of chain crowding in palisade layer may help to achieve more efficient solubilization of the PAs.