The complexation of β-cyclodextrin (β-CD) with cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) was investigated using molecular docking and M062X/6-31G(d,p) calculations. The calculations suggested two possible complex formations of 1:1 and 2:1 host-guest molecular ratio of β-CD with CBD and THC. The preferred orientation of all complexes in this study exhibited the hydrogen bonding between hydroxy-substituted benzene ring of CBD and THC with the β-CD’s secondary hydroxy groups at the wide rim. The calculated complexation energies indicate that formation of the 2:1 complexes (−83.53 to −135.36 kcal/mol) was more energetically favorable and chemically stable than the 1:1 complexes (−30.00 to −34.92 kcal/mol). However, the deformation energies of the host and the guest components in the 2:1 complexes (37.47–96.91 kcal/mol) are much higher than those in the 1:1 complexes (3.49–8.69 kcal/mol), which means the formation processes of the 2:1 complexes are more difficult due to the rigidity of the dimeric β-CDs. Therefore, the inclusion complexes of β-CD with CBD and THC are more likely to be in 1:1 host-guest ratio than in 2:1 molecular ratio. The results of this study supported the experimental results that the complexation constant of 1:1 β-CD/CBD (Ks = 300 M−1) is greater than that of 2:1 β-CDs/CBD (Kss = 0.833 M−1). Altogether, this study introduced the fitting parameters that could indicate the stability of the molecular fits in complex formation of each stoichiometry host-guest ratio, which are important for the assessment of the inclusion mechanisms as well as the relationships of reactants and products in chemical reactions.

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