Tumor necrosis factor (TNF) α can induce cell apoptosis and activate nuclear transcription (NF)‐κB in different cell types. Activated NF‐κB further promotes or suppresses cellular apoptosis in different cases. The present study explored the effect of activated NF‐κB on adipocyte apoptosis induced by TNFα and which microRNAs (miRNAs) were involved in the process. Our findings demonstrated that treatment of differentiated 3T3‐L1 adipocytes with TNFα (20ng/mL) rapidly activated NF‐κB and induced moderate apoptosis. Pyrrolidinedithiocarbamic acid (PDTC, 60µM), a specific NF‐κB inhibitor, abated NF‐κB activation that rendered the adipocytes vulnerable to TNFα‐induced apoptosis. Dozens of miRNAs exhibited significant expression changes following TNFα treatment and the addition of PDTC. In which, miRNA‐224‐5p (miR‐224) was up‐regulated by TNFα exposure but down‐regulated by PDTC addition. Furthermore, over‐expression of miR‐224 promoted NF‐κB activation and prevented the adipocyte apoptosis induced by TNFα, while miR‐224 deficiency showed the opposite effects. The TRAF‐associated NF‐κB activator (TANK) gene was identified as a direct target of miR‐224 by computational and luciferase reporter assays. Additionally, silencing the TANK gene by the small interfering RNA similarly promoted NF‐κB activation and attenuated the cellular apoptosis. In conclusion, these findings demonstrate that miR‐224 plays an essential role in adipocyte apoptosis caused by TNFα through control of NF‐κB activation via targeting the TANK gene. This article is protected by copyright. All rights reserved