Background: Giardia lamblia is the most common intestinal protozoan pathogen in human. This microorganism has a widespread distribution in the world and causes giardiasis. All chemical drugs that are available for the treatment of this infection have side effects. On the other hand, medicinal plants have shown promising effects in treating different kinds of parasitic diseases, including giardiasis. Origanum vulgare is a plant that has shown positive effects in the treatment of giardiasis in animal studies and in vitro. The purpose of this investigation was to examine how the flavonoids from the plant impact the key Giardia pathway. Methods: The Giardia parasite depends heavily on the arginine dihydrolase pathway to produce ATP, which is essential for its survival. This metabolic process enables the parasite to generate up to seven to eight times more energy from arginine than from glucose, making it the most critical pathway for Giardia's survival. To study this pathway, we performed pairwise molecular docking between various flavonoids and the virulence factors. Afterward, they assessed the characteristics of each flavonoid, such as toxicity, absorption, distribution, metabolism, and excretion, using the Swiss-ADME Webserver. Results: According to the findings of the molecular docking studies, three flavonoids (luteolin, 7- glucuronide, Naringin and Rutin) extracted from Origanum vulgare plant exhibited superior performance and are worth exploring for drug design purposes. It is worth noting that none of these three flavonoids demonstrated notable toxicity. Conclusion: This study suggests that the flavonoids luteolin, 7-glucuronide, Naringin and Rutin extracted from the Origanum vulgare plant could be potential candidates for drug design against Giardia lamblia. These flavonoids showed superior performance in inhibiting the critical virulence factors of the parasite without showing any significant toxicity. Further studies are necessary to evaluate their efficacy
