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Nitrogen-containing atoms in their core structures have been exclusive building blocks in drug discovery and development. One of the most significant and well-known heterocycles is the 1,3,4-thidiazole nucleus, which is found in a wide range of natural products and therapeutic agents. In the present work, certain <i>tris</i>-1,3,4-thiadiazole derivatives (<b>6</b>, <b>7</b>) were synthesized through a multi-step synthesis approach. All synthesized compounds were characterized using different spectroscopic tools. Previously, thiadiazole compounds as anti-<i>Toxoplasma gondii</i> agents have been conducted and reported in vitro. However, this is the first study to test the anti-<i>Toxoplasma gondii</i> activity of manufactured molecular hybrids thiadiazole in an infected mouse model with the acute RH strain of <i>T. gondii</i>. All the observed results demonstrated compound (<b>7</b>)’s powerful activity, with a considerable reduction in the parasite count reaching 82.6% in brain tissues, followed by liver and spleen tissues (65.35 and 64.81%, respectively). Inflammatory and anti-inflammatory cytokines assessments proved that Compound 7 possesses potent antiparasitic effect. Furthermore, docking tests against <i>Tg</i>CDPK1 and ROP18 kinase (two major enzymes involved in parasite invasion and egression) demonstrated compound <b>7</b>’s higher potency compared to compound <b>6</b> and megazol. According to the mentioned results, <i>tris</i>-1,3,4-thiadiazole derivatives under test can be employed as potent antiparasitic agents against the acute RH strain of <i>T. gondii</i>.