Infection with cryptosporidiosis endangers the lives of many people with immunodeficiency, especially HIV patients. Nitazoxanide is one of the main therapeutic drugs used to treat cryptosporidiosis. However, it is poorly soluble in water, which restricts its usefulness and efficacy in immunocompromised patients. Surfactants have an amphiphilic character which indicates their ability to improve the water solubility of the hydrophobic drugs. Our research concerns the synthesis of new cationic Gemini surfactants that have the ability to improve the solubility of the drug Nanazoxide. So, we synthesized cationic Gemini surfactants. N1,N1,N3,N3-tetramethyl-N1,N3-bis(2-octadecanamidoethyl)propane-1,3-diaminium bromide (CGSPS18) and 2,2‘-(ethane-1,2-diylbis(oxy))bis(N-(2-octadecanamidoethyl)-N,N-dimethyl-2-oxoethane-1-aminium) dichloride (CGSES18) and the detection of their chemical composition by spectroscopic methods, as well as studying the properties of their surfaces and their toxicity. Furthermore, the efficacy of nitazoxanide in infected mice was studied in conjunction with three different doses of surfactants. To assess the effect of nitazoxanide and surfactants, the infection was parasitologically counted before and after treatment, and the intestinal, liver, and lung tissues were also examined histopathologically. In this study, it was found that the combination of the drug nitazoxanide with surfactants, especially the compound (CGSPS18) at a concentration of 25% increased the efficacy and resulted in a percentage reduction of 90.8%. Histopathological examination revealed that the group treated with the drug nitazoxanide in combination with CGSPS18 showed the best results exhibiting an almost normal villous pattern. This study demonstrated an increase in the effectiveness of nitazoxanide when combined with surfactants, and this suggests a promising future for the use of surfactants as an adjunct to enhance the effectiveness of nitazoxanide for the treatment of cryptosporidiosis in immunocompromised patients, particularly HIV patients.