The elucidation of the underlying molecular mechanism of H2O2‑induced adipocyte differentiation in mesenchymal stem cells (MSCs) is important for the development of treatments for metabolic diseases. The aim of the present study was to identify microRNA (miR)‑330‑5p, which targets retinoid X receptor γ (RXRγ) and to determine the function of H2O2‑induced adipogenic differentiation of MSCs. During differentiation of MSCs into adipocytes induced by H2O2, miR‑330‑5p expression was decreased with a concomitant increase in RXRγ expression. A luciferase assay with RXRγ 3'‑untranslated region (UTR) reporter plasmid, including the miR‑330‑5p‑binding sequences, identified that the introduction of miR‑330‑5p decreases luciferase activity. However, it did not affect the activity of mutated RXRγ 3'‑UTR reporter. Enforced expression of miR‑330‑5p significantly inhibited adipocyte differentiation by decreasing RXRγ mRNA and protein levels. In contrast, inhibition of the endogenous miR‑330‑5p promoted the formation of lipid droplets by rescuing RXRγ expression. Furthermore, the effects of inhibition of RXRγ were similar to those of overexpression of miR‑330‑5p on H2O2‑induced adipogenic differentiation from MSCs. miR‑330‑5p inhibits H2O2‑induced adipogenic differentiation of MSCs, and this is dependent on RXRγ. Taken together, the results of the present study revealed that miR‑330‑5p acts as a critical regulator of RXRγ, and is able to determinate the fate of MSCs to differentiate into adipocytes. This suggests that miR‑330‑5p and RXRγ may be target molecules for controlling metabolic diseases.