Ovarian cancer is the most lethal gynecological cancer in the United States. Despite responding well to initial treatment, most patients relapse within 24 months. This relapse may be caused by cancer stem-like cells (CSCs) which resist initial chemotherapy and seed new heterogeneous tumors. Non-canonical NF-κB has previously been implicated in supporting CSCs, but the mechanism by which it does this is not understood. In this study we show that TWEAK and its receptor Fn14 are strong inducers of the non-canonical NF-κB pathway and that they are both enriched after chemotherapy. We go on to show that TWEAK/Fn14/RelB signaling enhances CSC features and phenotypes, including spheroid formation, asymmetric division, SOX2 expression, and the expression of EMT genes VIM and ZEB1. We also show that TWEAK treatment in combination with carboplatin enriches the CSC marker CD117, both by promoting CSC formation and by sensitizing non-CSCs to apoptosis. Inhibition of the TWEAK/Fn14/RelB axis in i.p. mouse model significantly prolonged overall survival when given as maintenance therapy post-chemotherapy. These results implicate TWEAK and Fn14 as factors which contribute to ovarian cancer relapse which could be explored for therapeutic development.