In the present work the adsorption of doxorubicin (DOX) on the surface of single-walled carbon nanotubes (SWCNTs) as well as its encapsulation in SWCNTs, and their dependence on the protonation of the NH₂ group of DOX, solvent, and the diameter of armchair (n, n) SWCNTs were systematically investigated using theoretical methods such as PM6-DH2 and M06-2X in the scheme of OMIOM. It was found that the two loadings, adsorption on the sidewall of CNTs and encapsulation in CNTs, have distinct solvent, protonation and diameter dependences. The encapsulation is much stronger than the adsorption of DOX on the sidewall of CNTs, and the former also has significantly higher solvent and protonation effects than the latter. The adsorption primarily occurs through π–π stacking and just becomes slightly stronger as the diameter of the CNTs increases, while besides the π–π stacking the additional C–H/N–H/O–H⋯π and CO⋯π also contribute to the encapsulation of DOX in CNTs. It seems that (8, 8) CNT with a diameter of ∼ 11 Å is energetically an onset for the encapsulation, since the encapsulation turns from endothermic to exothermic when the diameter is larger than approximately 11 Å, and the optimal diameter for the encapsulation is 14 Å corresponding to (10, 10) CNT. Thus for the thick CNT the encapsulation may also play an important role in the loading and releasing for the CNT-based drug delivery system of the DOX.