The creek begins in Brampton, and flows through the community of Malton (now part of Mississauga); it continues southeast, past Toronto Pearson International Airport; and through a shallow valley surrounded by the urban neighbourhoods of Islington and Mimico. The creek is often encased in a concrete spillway to contain the fast flowing water that occurs during rainstorms. Mimico Creek crosses Bloor Street near the Islington Subway Station, and empties into Lake Ontario about 1,000 metres (3,300 ft) west of the mouth of the Humber River.
Originally the creek had dozens of small tributary streams, the largest of which was Bonar Creek, that joined Mimico Creek near its mouth. Most of the tributaries were less than one kilometer long.
In the late 1970s and early 1980s, Humber Bay Park was constructed at the mouth of Mimico Creek. The park consists of two headlands, built using landfill from local construction projects, that flank the mouth. As a result, Mimico Creek is sometimes mistaken for the Humber River.