Background: Poloxamers are promising biomaterials for drug delivery applications due to their ability to enhance biopharmaceutical properties. Methods: This study focused on designing solid dispersions of ivermectin using poloxamer 407 by the fusion method and evaluating how variables of synthesis affect the polymer’s behavior and the resulting biopharmaceutical properties of ivermectin. Poloxamer 407 was selected based on a solubility test of preformulation studies. Initially, eight formulations were developed using different synthesis conditions, including polymer proportion, cooling gradient, and final process temperature. These were assessed by several characterization studies. Finally, saturation solubility dissolution profiles and in vitro drug release were also evaluated. Results: A combination of techniques confirmed the compatibility between poloxamer 407 and ivermectin in the solid dispersions. The rate of temperature in the cooling process of synthesis showed a significant impact on the polymer self-assembly, affecting their ability to entrap ivermectin. The optimized solid dispersion comprised ivermectin and poloxamer 407 in a 1:1 w/w ratio prepared by rapid cooling. This decrease in the crystallinity index and the nanometric size of particles of the solid dispersions could explain their ability to improve 1600-fold the aqueous solubility, as well as enhance the drug dissolution and in vitro drug release compared to pure ivermectin. Conclusions: Therefore, it follows that these poloxamer-based solid dispersions are promising alternatives to improve the bioavailability of ivermectin.