<p>A combined density functional theory (DFT) with experimental study have been performed for the physico-chemical characterization of the inclusion complexes of β-cyclodextrin (βCD) with painkillers viz. meloxicam (Mx) and piroxicam (Px) belonging to the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) group. The theoretical results are well in agreement with the experimental observations. From the calculations of various electronic properties, the high stability of the inclusion complexes has been ensured. These facts have been reconfirmed from the experimental studies showing that the βCD-Px and βCD-Mx complexes can tolerate large changes in bulk pH, without breaking apart. pH-dependent absorption studies demonstrated the stability of the complex over a broad pH range (2.5–11.5), suggesting robustness under physiologically relevant conditions. Kinetic analysis using time-resolved fluorescence measurements indicated enhanced interaction dynamics in the presence of β-cyclodextrin. The encapsulation of these drugs has also been followed by spectroscopic techniques. ITC experiment has been used to determine the binding constants and thermodynamic parameters of the complexation process. The protective effect of βCD host on βCD-NSAIDs inclusion complexes is shown by the reduction in permeabilization/leakage of membrane bilayer compared to the bare drugs. This is reflected in the rates and extent of leakage of inner aqueous content of SUVs formed by DMPC-DMPE using Tb³⁺/DPA fluorescence assay. Since the permeabilization/leakage reflects the extent of perturbation, reduced membrane perturbation upon encapsulation in βCD could reduce the damage in the GI tract and thereby, increase the clinical efficacy of the drugs.</p> Graphical abstract <p></p>