To study the influence of pore structural properties of metal−organic frameworks (MOFs) on drug adsorption and delivery, we synthesized two MOF termed TMU-6(RL1) {[Zn-(oba)(RL1) 0.5 ] n •(DMF) 1.5 } and TMU-21(RL2) {[Zn(oba)-(RL2) 0.5 ] n •(DMF) 1.5 } with amine basic N-donor pillars containing phenyl or naphthyl cores with various hydrophilic properties around the main center of the reaction. TG, IR, XPS, and PXRD analyses were used to extensively characterize the MOFs. The synthesized carriers showed high adsorption efficiency, stability, and controlled release. As an anticancer drug, Nimesulide (Nim) was adsorbed to MOFs using multiple adsorption mechanisms, such as Host π−π Guest interaction and Host N−H•••O Guest hydrogen bonds. Moreover, Hirshfeld surface analysis showed when the benzene core was replaced with the naphthalene core, the percentage of intermolecular interactions of π•••π and N•••H by amine sites in TMU-21( RL2) decreased compared with TMU-6(RL1), while the percentage of these interactions with guest molecules increased. The results showed that changes in the hydrophobicity/ hydrophilicity properties of MOFs would alter their ability to adsorb Nim in the pore of the frameworks. In vitro anticancer studies also showed that the cytotoxicity of Nim in MOFs@Nim composites against human cervical cancer cell line (HeLa cells) and human colon cancer cell line (HT-29 cells) is much higher than that of free Nim. Generally, based on the results, it can be said that the biological behavior of carriers can be regulated by adjusting the structure properties of MOFs.