Renal cell carcinoma (RCC) is a common kidney disease associated with high mortality. Sorafenib is a protein kinase inhibitor that targets multiple kinases and is used for treating different cancers, including RCC. However, sorafenib resistance in patients with RCC hampers its use. Therefore, elucidating the molecular mechanisms underlying sorafenib resistance in RCC and developing novel therapeutic strategies to overcome drug resistance are vital. In this study, we found that the expression level of the long noncoding RNA (lncRNA) E2F1 messenger RNA stabilizing factor (EMS) was significantly higher in sorafenib-resistant RCC tissues and cell lines than in sorafenib-sensitive RCC tissues and cell lines. lncRNA EMS knockdown improved the sensitivity of sorafenib-resistant RCC cells to sorafenib treatment, as evidenced by decreased cell proliferation and increased apoptosis. Additionally, lncRNA EMS silencing combined with sorafenib treatment markedly inhibited RCC tumor development in vivo. Moreover, it was systematically shown that lncRNA EMS sponged miR-363-3p, whose expression was decreased in sorafenib-resistant RCC. Notably, miR-363-3p negatively regulated the expression of dual-specificity phosphatase 10 (DUSP10) by targeting its 3'-UTR. Furthermore, miR-363-3p overexpression restored sorafenib sensitivity, whereas upregulated DUSP10 expression promoted sorafenib resistance in sorafenib-resistant cell lines. In conclusion, the lncRNA EMS/miR-363-3p/DUSP10 axis regulates sorafenib resistance in RCC, and these molecules are promising biomarkers and therapeutic targets for patients with sorafenib-resistant RCC.