Previous studies have shown sorafenib to function as a multitargeted tyrosine kinase inhibitor in different tumors. However, whether sorafenib improves renal cell carcinoma (RCC) through activating transcription factor 4 (ATF4) has never been explored. In the current study, we showed that sorafenib could suppress RCC cell viability in a time- and dose-dependent manner. Furthermore, sorafenib is demonstrated to enhance the mRNA and protein levels of ATF4. Meanwhile, overexpression of ATF4 was demonstrated to induce ACHN cell cycle arrest and cell apoptosis. Moreover, treatment with sorafenib could enhance the expression of CCAAT/enhancer-binding protein-homologous protein (CHOP) and p53 upregulated modulator of apoptosis (PUMA), thereby leading to ACHN cell apoptosis. More importantly, silencing of ATF4 could largely abolish sorafenib-induced upregulation of CHOP and PUMA in ACHN cells. Meanwhile, sorafenib-induced cell apoptosis may be dependent on the activation of ATF4 since knockdown of ATF4 partially reversed sorafenib-induced ACHN cell apoptosis. In summary, the present study demonstrates that sorafenib activates ATF4-CHOP-PUMA pathway in RCC cells, resulting in enhanced ER stress-related cell apoptosis.