Nitazoxanide (NTZ) is a highly hydrophobic nitrothiazolyl-salicylamide that displays antimicrobial activity against a variety of parasites, anaerobic bacteria and viruses. More recently, its effectiveness in the pharmacotherapy of chronic hepatitis, the leading cause of liver cirrhosis and hepatocellular carcinoma (HCC), has been reported. On the other hand, the extremely low aqueous solubility of the drug challenges its administration by different routes. The present work explored for the first time the encapsulation of NTZ within pristine, lactosylated and mixed poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) polymeric micelles (PMs) of different architectures, molecular weights and hydrophilic-lipophilic balance (HLB) as a strategy to improve its aqueous solubility and to potentially target it to the liver parenchyma. The solubility was increased up to 609 times. The drug encapsulation modified the self-aggregation pattern of the different amphiphiles, resulting in a sharp growth of the micellar size. The encapsulation capacity of the lactosylated derivatives was smaller than that of the pristine counterparts, though the development of mixed PMs that combine a highly hydrophilic lactosylated amphiphile (e.g., poloxamer F127 or poloxamine T1107) that forms the micellar template and a more hydrophobic unmodified poloxamine (T904) that increases the hydrophobicity of the core resulted in the synergistic encapsulation of the drug and a substantial increase of the physical stability over time. Overall findings confirmed the extremely great versatility of the poloxamer/poloxamine mixed self-assembly systems as Trojan nanocarriers for the encapsulation of NTZ towards its targeting to the liver.