Although quercetin is an effective bioactive compound preventing the progress of several human cancers, its impact is reduced due to low bioavailability. The therapeutic potential of quercetin can be enhanced by its encapsulation with macromolecules. In the current study, stable complexes of water-solublep-sulfonato calix[4,8]areneN,N-dimethylamine derivatives (calix[4]arene (T-4) and calix[8]arene (O-4)) with quercetin (C-1andC-2) were synthesized and thoroughly characterized, and their cytotoxic effects were evaluated. The first phase solubility study performed shows that the solubility of quercetin is improved because of the formation of the inclusion complex. The solubility constant (Ks) values ofT-4-quercetinandO-4-quercetincomplexes were calculated to be 205.77 mM and 111.85 mM, respectively.In vitrocytotoxic assays of both complexes on different cancer cell lines were performed by using an alamarBlue assay. Acquired data revealed that the cytotoxic potential of complexesC-1andC-2was increased by 3.95 and 2.98-fold, respectively, compared to quercetin. Molecular docking and molecular dynamics simulations of the complexes were also performed to predict the three-dimensional structure of host-guest interactions as well as to obtain crucial time-dependent insight into the calixarene and quercetin complex formation dynamics.