We attempted to explore the effect of Rho guanine nucleotide exchange factor 39 (ARHGEF39) on the phenotypes of clear cell renal cell carcinoma (ccRCC) cells and the underlying mechanism. Analyses of the data from The Cancer Genome Atlas (TCGA) illustrated that ARHGEF39 expression was upregulated in ccRCC and high ARHGEF39 expression was correlated with a worse prognosis. The mRNA and protein expression of ARHGEF39 in ccRCC and nontumorigenic cells was measured by qRT-PCR and western blotting, respectively. The results showed that ARHGEF39 expression was upregulated in ccRCC cells compared with nontumorigenic cells. CCK8 and clonogenic assays were used to measure the viability of ccRCC cells after knockdown or overexpression of ARHGEF39. Transwell assays were used to examine the changes in cell motility after alterations in ARHGEF39 expression and treatment with LY294002 (an AKT inhibitor) or PD98059 (an ERK inhibitor). ARHGEF39-mediated changes in the phosphorylation of AKT and ERK were measured by western blotting. The results indicated that ARHGEF39 promoted the viability, migration and invasion of ccRCC cells by regulating the activation of the AKT/ERK signaling pathway. Overall, our research suggested that ARHGEF39 was upregulated in ccRCC and possibly facilitated the malignant development of ccRCC by modulating the AKT/ERK signaling pathway.