Fenbendazole is an antiparasitic drug widely used in veterinary medicine to treat parasitic infections caused in animals like cattle, horses, sheep, and dogs. Recently, it has been repositioned as a potential alternative for cancer treatment. However, it is a highly hydrophobic molecule (0.9 ug/mL), which can compromise its dissolution rate and absorption. Thus, this work aimed to apply a nanotechnological approach to improve drug solubility and dissolution performance. Fenbendazole nanoparticles stabilized by different poloxamers were obtained by lyophilization without cryoprotectants. The behavior of the drug in the solid state was analyzed by X-ray diffractometry, differential scanning calorimetry, and infrared spectroscopy. The nanosystems were also evaluated for solubility and dissolution rate. A long-term stability evaluation was performed for three years at room temperature. The yields of the lyophilization ranged between 75 and 81% for each lot. The nanoparticles showed a submicron size (< 340 nm) and a low polydispersity depending on the stabilizer. The physicochemical properties of the prepared systems indicated a remarkable amorphization of the drug, which influenced its solubility and dissolution performance. The drug dissolution from both the fresh and aged nanosystems was significantly higher than that of the raw drug. In particular, nanoparticles prepared with poloxamer 407 showed no significant modifications in their particle size in three years of storage. Physical stability studies indicated that the obtained systems prepared with P188, P237, and P407 suffered certain recrystallization during long storage at 25 °C. These findings confirm that selected poloxamers exhibited an important effect in formulating fenbendazole nanosystems with improved dissolution.