The interaction of 4-nerolidylcatechol (4-NRC), a potent antioxidant agent, and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated by the solubility method using Fourier transform infrared (FTIR) methods in addition to UV–Vis, 1H-nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. The inclusion complexes were prepared using grinding, kneading and freeze-drying methods. According to phase solubility studies in water a BS-type diagram was found, displaying a stoichiometry complexation of 2:1 (drug:host) and stability constant of 6494 ± 837 M−1. Stoichiometry was established by the UV spectrophotometer using Job's plot method and, also confirmed by molecular modeling. Data from 1H-NMR, and FTIR, experiments also provided formation evidence of an inclusion complex between 4-NRC and HP-β-CD. 4-NRC complexation indeed led to higher drug solubility and stability which could probably be useful to improve its biological properties and make it available to oral administration and topical formulations.