Background: The susceptibility of Blastocystis spp.to standard antimicrobials is not clear. The development of resistant strains against the recommended drugs has evoked the importance of using an alternative medicine. Metronidazole constitutes a mainstay and is considered the first line for treatment, yet, it is complicated with many drawbacks. The demand for finding alternatives introduced nitazoxanide (NTZ) and natural products to provide successful new regimens for treatment and to avoid resistant infections. Objective: The present study was conducted to evaluate the anti-Blastocystis effects of Boswellia serrata compared to NTZ on experimentally infected mice. Material and Methods: Three groups of BALB-c mice were used: untreated control group (G1); infected mice treated with NTZ (G2); infected mice treated with B. serrata (G3). Histopathological examination of colonic epithelium and immunohistochemical assessment was done for detection of TNF-α in the two groups of mice treated with B. serrata in comparison to those treated with NTZ. Results: The test appraised the effect of B. serrata which succeeded in maintaining the intact surface epithelium and goblet cells. The mononuclear infiltrations were markedly decreased in the lamina propria and appeared as small aggregates at the base of the crypts. The submucosa showed marked reduction of inflammatory cells. Occasional intraepithelial lymphocytes were detected in-between epithelial cells. The negative Periodic Acid-Schiff (PAS) reaction detected in the intestinal crypts was comparable to NTZ treatment. Surpassing NTZ, B. serrata-treated group showed an apparently less positive reaction to TNF-α in the cells of the submucosa and lamina propria, while NTZ effect was restricted only to the submucosa. Conclusion: This natural product can offer an alternative therapy for use instead of or concurrently with the conventional anti-Blastocystis treatment.