Ovarian cancer is one of the most common malignancies in women and characterized by a rapid progression to metastasis, which restricts effective treatment options. Caffeic acid phenethyl estre (CAPE), a natural honeybee product, exhibits a variety of biological activities, anti-tumor is included. Our study aims to explore whether CAPE could inhibit the progression of ovarian cancer and the underlying molecular mechanism. The establishment of ovarian cancer model was set up in mice through caudal vein injection of SKOV-3 cells. Results indicated that CAPE treatment remarkably decreased the viability, migration and invasion of SKOV-3 cells. Besides that, the apoptosis of SKOV-3 cells was significantly promoted by CAPE treatment. Moreover, the growth of ovarian cancer was tremendously inhibited by CAPE in vivo and its action was accompanied by the obstructed Ki67 and PCNA expression. Furthermore, nuclear factor kappa b (NF-κB) pathway was dramatically suppressed by CAPE through the inhibition of IκB phosphorylation, nuclear translocation of p65 and NF-κB p65 DNA binding activity. By contrast, cells transfected with p65 siRNA exhibited decreased cell viability, migration and invasion along with increased cell apoptosis in SKOV-3 cells. However, CAPE treatment could enhance these alters induced by p65 siRNA in KOV-3 cells. Taken together, these findings suggested that CAPE could restrain the progression of ovarian cancer via inactivating NF-κB signaling, and may provide novel therapeutic regimens for ovarian cancer.