Selecting a polymer depends on its characteristics, the properties of the drug and of the remaining ingredients in the formulation. The drug, when incorporated into a polymeric matrix, can show several advantages when compared with its conventional form. In this context, this work describes the preparation and characterization of polyethylene glycol (PEG 4000) and its derivative particles loaded with benznidazole, as well as evaluates their trypanocidal activity. In this work, reactions to modify the PEG 4000 polymer and the subsequent incorporation of the benznidazole were made. The nuclear magnetic resonance (NMR) analysis confirmed the efficiency in modifying the PEG chains. The morphology of polymeric films was observed by atomic force microscopy (AFM) and showed considerable changes on the film organization. The acetylation of PEG favored the stability of the system and an increase in the zeta potential from -14.83 to -25.54 mV was observed. Although encapsulation efficiency values between 30.14 and 39.48% were found, the enhanced benznidazole dissolution profile by microparticles enables the use of lower drug concentrations. This fact can be proven by the increased trypanocidal effect of benznidazole when encapsulated in BP3 microparticles. Finally, the high selectivity of the formulations for trypanocidal action guarantees their safety as an alternative for the treatment of the Chagas disease.