Objective: To investigate the effect of special AT-rich sequence-binding protein 2 (SATB2) gene and quercetin on the activity, invasion and apoptosis of renal cell carcinoma (RCC) and its mechanism. Methods: Human renal carcinoma 786-O cells were divided into blank group, recombinant pcDNA3.1-SATB2 group, quercetin group and pcDNA3.1-SATB2+quercetin group, in which pcDNA3.1-SATB2 was transfected according to Lipofectamine 2000. After 48 hours in culture, CCK-8, Transwell chamber and flow cytometry were used to detect cell viability, invasion and apoptosis. Western blotting was used to detect the expression of SATB2, STAT3, p-STAT3, MMP-2 and Bcl-2 protein. Results: The expression of SATB2 protein in 786-O cells transfected with pcDNA3.1-SATB2 increased significantly (P<0.05). pcDNA3.1-SATB2 and quercetin with different concentrations inhibited 786-O cell viability, quercetin also inhibited cell viability in a concentration and time dependent manner (P<0.05). pcDNA3.1-SATB2 and quercetin could inhibit the invasive ability of 786-O cells, induce apoptosis and down-regulate the expression of p-STAT3, MMP-2 and Bcl-2. The combination of pcDNA3.1-SATB2 and quercetin had more significant effects on the invasive ability, apoptosis and the expression of p-STAT3, MMP-2 and Bcl-2 of 786-O cells (P<0.05). Conclusion: Overexpression of SATB2 can enhance inhibition of cell viability and invasion and apoptosis promoting of quercetin on 786-O cells, which may be related to the inhibition of STAT3 signaling pathway.