Toxoplasmosis is a frequent disease with an estimated prevalence of more than one billion
human cases worldwide and over one million new infections each year. It is classified as
a neglected tropical disease by the CDC since 2019. The disease may pass unnoticed in healthy
individuals but could be fatal in the immunocompromised. Moreover, no effective treatment is
available against the chronic form of the disease. Available anti-Toxoplasma drugs are associated
with many side effects. Therefore, search for new more reliable, more efficient, and less
toxic therapeutic agents is a continuous endeavor. This study assesses the potential use of
nitrofurantoin, a compound with well-established antimicrobial properties, as a potential anti-
Toxoplasma drug in vivo. It compares its efficacy to the commonly used anti-Toxoplasma agent
spiramycin by molecular and histopathological methods in acute and chronic infection. The
results demonstrate a significant ability to eliminate the parasite (P < 0.001) whether used as
mono- or combined therapy with spiramycin in the acute and chronic stages. When compared
to the anti-Toxoplasma drug spiramycin, nitrofurantoin achieved similar efficacy in the acute
and chronic infection (P = 0.65 and P = 0.096, respectively). However, better results were
obtained when using a combination of both drugs (P < 0.001). Additionally, nitrofurantoin
showed good inhibitory effects on the inflammatory process in the liver, kidney, and uterus
of the experimentally infected animals. In conclusion, nitrofurantoin can be considered as
a potential anti-Toxoplasma agent. Nevertheless, further studies are recommended before
consideration for clinical trials.