The expression of death receptor 6 (DR6) is abnormal in some cancer types, but the function and underlying molecular mechanisms of DR6 in tumor progression are not yet clear. In the present study, our analysis of ovarian cancer RNA sequencing data from The Cancer Genome Atlas revealed that DR6 is upregulated in human ovarian cancer. We confirmed that the expression level of DR6 is upregulated in ovarian cancer tissues when compared with matched adjacent normal tissues. In addition, DR6 enhanced ovarian carcinoma cell migration ability, and decreased expression of DR6 inhibited the expression of matrix metalloprotease (MMP) 2 and MMP9, and increased the expression of E-cadherin. Additionally, DR6 shRNA caused a significant decrease in phosphoinositide-3-kinase (PI3K), phospho (p) -AKT, p-extracellular signal-regulated kinase (ERK), and p-mitogen-activated protein kinase kinase expression in SKOV3 cells. These results suggested that DR6 can enhance ovarian carcinoma cell migration ability through the mitogen-activated protein kinase/ERK and PI3K/AKT pathways. Notably, mass spectrometric analysis indicated that DR6 co-purified with kinesin family member 11 (KIF11), and we verified the interaction between KIF11 and DR6 by co-immunoprecipitation and glutathione S-transferase pull-down. Furthermore, we demonstrated that DR6 can bind tumor necrosis factor receptor-associated factor 4 (TRAF4) with co-immunoprecipitation. Overexpression of KIF11 or TRAF4 eliminated the suppression of carcinoma cell migration by DR6 knockdown. We also found that TRAF4 and KIF11 were upregulated in ovarian carcinomas and that their level of expression was positively correlated with that of DR6. The findings above suggest that DR6 may play a notable oncogenic role in ovarian malignancy by interacting with TRAF4 and KIF11, and that DR6 may be an effective therapeutic target in ovarian cancer.