Apixaban (APX) is an anticoagulant drug with poor aqueous solubility, limiting its bioavailability. This study investigates whether solubility can be enhanced by inclusion of APX within the native (α-, β-, and γ-) cyclodextrins (CDs). Phase solubility studies revealed an enhancement in solubility in the presence of β-CD. The complex formation constant for β-CD was found to be one order of magnitude higher than that of α-CD and γ-CD (K11 = 35, 268 and 41 M−1 for α-, β- and γ-CDs, respectively). 1H NMR spectra in DMSO confirmed the formation of the APX/β-CD complex in solution. Infrared (IR) spectroscopy and differential scanning calorimetry (DSC) confirmed the formation of an APX/β-CD inclusion complex in the solid state. Molecular dynamics (MD) simulations were employed to study the dynamics and host-guest interactions of APX with the CDs. MM-PBSA estimates of the binding free energies revealed a higher stability of the complex with β-CD compared to the other two, in agreement with the experimental results, with favorable van der Waals and electrostatic interactions, and with the former contributing much more significantly.