Abstract: Background: Blastocystis is the most common enteric protozoa in humans and animals worldwide. The hazardous side effects and potential development of drug resistance to the standard drug, metronidazole (MTZ), necessitate the search for safer and more efficient alternative therapeutics. Objective: The present study was designed to investigate the in vitro activity and in vivo efficacy of two natural medicinal compounds, Olive Leaf Extract (OLE) and Bee Pollen Compound (BPC) against subtype 3 Blastocystis isolated from symptomatic patients. Materials and Methods: Cultured parasites were challenged with a graded concentration of OLE (500, 1000 μg mL–1), BPC (500, 1000 μg mL–1) and MTZ (150, 250 μg mL–1) to assess its in vitro growth by counting the number of viable cells after one and two h of incubation and morphological ultrastructural changes were evaluated using Transmission Electron Microscope (TEM). The anti-Blastocystis effects of OLE and BPC were determined in 40 laboratory bred Swiss albino mice inoculated with Blastocystis isolates using parasitological, histopathological and immunohistochemical methods. Results: Blastocystis isolated from symptomatic patients were subtype 3. The OLE and BPC showed statistically significant (p<0.05) in vitro growth inhibition of Blastocystis in a concentration dependent manner and a statistically significant (p<0.05) in vivo reduction of the number of Blastocystis in stool samples and intestinal contents of infected treated mice higher than MTN effects with apoptotic-like death and Programmed Cell Death (PCD) in Blastocystis. The BPC normalized villous architecture and increased local IgA secretory villous cells. Conclusion: These findings highlighted the potential therapeutic effects of OLE and BPC as potent safe natural alternatives against blastocystosis. The BPC was superior to OLE in ameliorating the severity of tissue pathology and had an immunostimulatory effect on intestinal cells.