Background Complement component 1 Q subcomponent binding protein (C1QBP) is a multifunctional protein and plays a vital role in the progression and metabolism of cancer. Our previous study has revealed that the low expression of C1QBP in renal cell carcinoma (RCC) and knockdown of C1QBP promotes the adhesion and invasion of RCC cells. However, its functions in the metabolism, oxidative stress and apoptosis of RCC cells have not yet been explored. Methods Metabolomics assay was applied to investigate the role of C1QBP in RCC metabolism. C1QBP knockdown and overexpression cells were established via lentiviral infection and subjected to apoptosis and ROS assay in vitro. RNA stability assay and pre-mRNA detection were applied to characterize the mechanism of C1QBP regulating XDH transcription. In vivo, orthotopic tumor xenografts assay was performed to investigate the role of C1QBP progression. Results Metabolomics investigations revealed that C1QBP dramatically diminished the hypoxanthine content in RCC cells. C1QBP promoted the mRNA and protein expression of hypoxanthine catabolic enzyme xanthine dehydrogenase (XDH). Meanwhile, C1QBP regulated the expression of XDH gene at the pre-transcriptional level by regulating XDH transcriptional stimulators IL-6, TNF-α and IFN-γ. Moreover, the expression of C1QBP and XDH was lower in RCC tumors compared with the para-tumor normal tissues, and their down-regulation was associated with higher levels of Fuhrman grade. In RCC cells, C1QBP significantly increased produces reactive oxygen species (ROS) levels, apoptosis, and the expression of apoptotic proteins cleaved caspase-3 and bax/bcl2 via regulating XDH.Conclusions C1QBP promotes the catabolism of hypoxanthine and elevates the apoptosis of RCC cells by modulating XDH-mediated ROS generation.