Objective: Drugs that have already been clinically approved for conditions other than cancer, but are found to possess previously unrecognized cytotoxicity towards malignant cells, may serve as potential anti-cancer candidates. Fenbendazole is a broad-spectrum benzimidazole anthelminthic approved for use in humans with a high safety margin and low degree of toxicity. In the present study, we assessed the inhibitory activity of fenbendazole towards human ovarian cancer cells and animal models with cell-line xenografts that showed differential effects by the administration routes. Methods: Human ovarian cancer cell lines, including A2780, HeyA8, and SKOV3, as well as normal cell lines, including IOSE, 293T, and HUVEC were used in in vitro experiments. The MTT assay was performed to evaluate the cell viability that were given fenbendazole. Fenbendazole was also given to animal models with cell-line xenografts with A2780 and HeyA8 by orally, intraperitoneally, or intravenously in either form of the drug itself alone or as a combined polymer with poly lactic-co-glycolic acid (PLGA), a delivery vehicle for the drug. The mean tumor weights were compared to assess the anti-cancer activity. Results: Fenbendazole decreased cell viability in all three types of cancer cell lines as well as normal cell lines in vitro suggesting its non-specific anti-proliferative effects. When it was given to the animal models orally, fenbendazole did not affect the tumor weights compared to the control group (Dosing of fenbendazole 1 mg/mouse and 10 mg/mouse). The anti-cancer activity was also absent when it was given to the animal models intraperitoneally by demonstrating similar tumor weights between the experimental and control groups (Dosing 1 mg/mouse and 10 mg/mouse). Intraperitoneal injection of fenbendazole as a combined polymer with PLGA did not affect the tumor weights either, but rather formed solid aggregates in the peritoneal cavity without being absorbed (Dosing 1 mg/mouse). When the drug was injected intravenously with PLGA, however, the tumor weights significantly decreased in comparison to the animal models that were given PLGA alone (0.59±0.23 g in fenbendazole-PLGA group vs. 1.11±0.52 g in PLGA group, p-value < 0.05) (Figure 1). The body weights of the animal models remained similar between the experimental and control groups. Conclusion: Fenbendazole demonstrated anti-cancer activity in human epithelial ovarian cancer cell lines in vitro. However, this effect was not demonstrated in animal models when it was given orally or intraperitoneally due to its poor absorption arising from the drug’s hydrophobic characteristics. When it was given in the form of combined polymer with PLGA intravenously, however, its anti-cancer activity was maintained, which warrants further investigation of the potential anti-cancer effects of fenbendazole and enhanced modes of delivery.