Background and study aim: Toxoplasma gondii is a globally distributed parasite that causes oxidative stress as a part of the mechanism of neuropathology. The currently available treatments for toxoplasmosis are of limited efficacy because of its distinct pathophysiology. This study aimed to assess the anti-inflammatory and antioxidant effects of Lepidium sativum seed extract, olive leaves extract, resveratrol, and Eucalyptus either as a monotherapy or in combination with pyrimethamine-sulfadiazine in experimental histopathological toxoplasmosis by and immunohistochemical studies. Patients and Methods: One-hundred seventy-six Swiss albino mice were divided into eleven experimental groups (16 mice each) as follows Group (1) Control non-infected, Group (2) Control infected, Group (3) infected and treated with pyrimethamine-sulfadiazine, Group (4) infected and treated with RSV, Group (5) infected and treated with Eucalyptus, Group (6) infected and treated with Lepidium sativum, Group(7) infected and treated with olives leaves extract, Group (8) infected and treated with pyrimethamine-sulfadiazine and RSV, Group(9) infected and treated with pyrimethamine-sulfadiazine and Eucalyptus, Group (10) infected and treated with pyrimethamine-sulfadiazine and Lepidium sativum, Group (11) infected and treated with pyrimethamine sulfadiazine and olives leave extract. Results: Histopathological examination of liver and brain tissues displayed marked improvement in all treated groups with a significant effect on the expression of iNOS and NSE, mainly in olives leaves extract treated groups. Conclusion: Olive leaf extract, Lepidium sativum seed extract, resveratrol, and Eucalyptus can be promising efficient natural alternatives that can ameliorate the histopathological changes and oxidative stress triggered by the parasite during Toxoplasma gondii infection.