Prohibitin-2 (PHB2) serves as a key signalling protein that is connected with diverse cellular functions. PHB2 overexpression frequently occurs in cancers and is closely related to tumorigenesis. So far, the connection between PHB2 and renal cell carcinoma (RCC) has not been discussed yet. The purpose of this study was to explore the expression and biological function of PHB2 in RCC and to uncover the underlying mechanisms. High level of PHB2 was found in RCC tissues, and this overexpression was linked to a worse overall survival rate for RCC patients. In RCC cell, the lowering of PHB2 generated tumour-inhibiting effects in RCC cells such as proliferation retardation, cell cycle arrest, suppression of the capacity for metastasis, and chemosensitivity enhancement. Mechanistically, PHB2 mediated the activation of eukaryotic initiation factor 4E (eIF4E) and the translation of oncogenic proteins via the regulation of MNK. The inhibition of MNK diminished the effects of PHB2 on eIF4E-medited oncogene translation. The overexpression of eIF4E reversed PHB2-reduction-evoked tumour-inhibiting effects. Moreover, RCC cells with decreasing PHB2 exhibited a weakened ability to form xenografts in vivo. In conclusion, these findings show that PHB2 is pivotal for RCC progression and suggest that inhibiting MNK/eIF4E by decreasing PHB2 is a potential pathway for the treatment of RCC.