Background: The present study was designed to investigate the antigiardial efficacy of low metronidazole dose loaded-D.L-lactide-co-glycolide (LMD-PLGA) nanoparticles (NPs) and to compare it with the standard high dose of metronidazole either free (HMD) or loaded on PLGA (HMD-PLGA). Materials and Methods: PLGA NPs were prepared by single emulsification method, metronidazole (MTZ) was loaded in low and high doses. The nanoparticles were evaluated in vivo for mice model. The Giardia intestinalis infected mice were treated by LMD and HMD either free or PLGA NPs loaded, the parasitic load and ployclonal antigiardial serum antibodies (IgG and IgA) were recorded. Histopathological studies on intestinal and liver sections were applied. Results: MTZ-PLGA NPs was successfully prepared with 81.68% encapsulation efficiency and with an average particle size of approximately 228.00 ± 43.19 nm and -32.28 ± 0.07 mV Zeta potential. Experimentally, it was observed that Giardia intestinalis infected animals administered with LMD-PLGA had completely eliminated cyst shedding and trophozoite count compared with Giardia-infected mice. Further, it was found that animals belonging to LMD-PLGA group had significantly reduced levels of antigiardial IgA (0.99 ± 0.05) antibodies in serum compared with Giardia-infected. Histopathologyically, also animals belonging to LMD-PLGA treated group had intact mucosal epithelium lining, and normal villi with no detection of G. intestinalis trophozoites. In addition to the less toxic effect on the liver tissue compared to free HMD, HMD-PLGA and infected-untreated groups using Ishak grading system. Conclusion: Our study showed that PLGA nanoparticles could be atrial delivery systems for antigiardial drugs to improve their therapeutic efficacy and minimize their side effects that results from frequent dosing.