Background: Use of the therapeutic drug co-trimoxazole (sulfamethoxazole/trimethoprim) against acute toxoplasmosis is limited highlighting the need for new, effective and secure treatments. Natural products gained significant attention as effective and potentially safer alternatives for the treatment of parasitic diseases. Objective: To assess the potential efficacy of Origanum vulgare extract (Oregano) for the treatment of T. gondii (RH strain)-experimentally infected mice, in comparison to co-trimoxazole. Material and Methods: Four groups of Swiss albino male mice were included in the study, (12 mice in each): non-infected, infected non-treated, co-trimoxazole treated, and oregano treated. Treatment was started on the 1st day post infection (dpi) and mice were sacrificed at the 7th day. Therapeutic effects were evaluated by conducting parasitological, and histopathological studies. To assess cytotoxicity, liver enzymes were determined. To explore the potential mechanism of action, cyclooxygenase 2 (COX-2) immunohistochemical staining of liver tissues was performed. Results: Treatment with oregano extract or co-trimoxazole significantly exhibited anti-T. gondii effects compared to the untreated as evidenced by reduced tachyzoite counts in the peritoneal fluid, reduced mortality rate, improved histopathological changes of liver, spleen and brain tissues, and reduced COX- 2 immunohistochemical staining in liver sections. Additionally, oregano extract presented a noticeable improvement in liver enzyme levels. Conclusion: From the results obtained, the potential therapeutic efficacy of oregano extract against acute toxoplasmosis was concluded.