The purpose of this study was to develop an efficient strategy to use laponite (LAP) nanoplates as a platform for the efficient release of anionic dexamethasone (DEX). Results revealed that DEX was encapsulated into the interlayer space of LAP nanodisks through an intercalation process with a high loading efficiency of 95.10 ± 0.80%. X-Ray diffraction (XRD) patterns and Fourier transform infrared (FTIR) spectra of the hybrid LAP/DEX nanoplates (LD-NPs) indicated that DEX molecules could successfully adsorb into the LAP nanoplates depending on the pH value. Moreover, in vitro drug release study showed that the release of DEX from LD-NPs was pH-dependent, and DEX released at a faster rate at acidic pH (pH = 5.4) than physiological one. Importantly, the results of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay confirmed that the released DEX from LD-NPs not only did not show cytotoxic effect but also improved the viability of MG63 cells compared to LAP-free samples (DEX enriched medium). Our work indicated that LAP nanoplates could be a promising candidate for release of anionic DEX in the controlled manner depending on the pH environment. Moreover, the merits of LD-NPs such as good cytocompatibility, excellent physiological stability and sustained pH-responsive release properties, make them a promising platform for the delivery of other therapeutic agents beyond DEX.