Oregano leaves (Origanum vulgare) are potentially known as antibacterial agent. Colibacillosis is an infectious disease caused by Escherichia coli as the primary agent. Besides that, E.coli reported inducing various other systemic diseases that harm human health and the economy due to the massive transmission of bacteria in humans and livestock. This study investigated the potential use of oregano leaves to overcome the growth of E. coli in the colibacillosis mice model. Mice were infected with the E. coli, then administered with oregano leaf extract with increasing doses of 5mg/kg BW, 10mg/kg BW, and 20mg/kg BW. The spleen was collected and the histopathology and histomorphometry were analyzed. Administration of oregano leaf extract showed the potential to significantly reduce the rate of tissue damage (p<0.05) through the reduction of the size of white pulp, an indicator of the immune system's active resistance in overcoming pathogenic bacterial infections. It can be concluded that oregano extract improved the white pulp enlargement of spleen.