Archaeological evidence suggests that Native peoples had been attracted to the Credit River Valley over thousands of years. At the time of European contact in 1615, both Iroquoian and Algonquian speaking peoples inhabited this area. By 1700, an Ojibwa (Anishnabe) group known as the Mississaugas had driven the Iroquois from the north shore of Lake Ontario. The name "Mississauga" is believed to mean "river of the north of many mouths," referring to a river in Northern Ontario which drained into Lake Huron. It was from this part of Ontario that the Mississaugas had traveled in the late 17th century.

In the 1720s, the French established many trading posts around Lake Ontario, one of which was located near the mouth of the Credit River. The river was named Rivière au Crédit by French fur traders, because trading goods were supplied to the native Mississaugas in advance (on credit) against furs which would be provided the following spring. After a decline of French power in the region, the British continued to trade with the Natives. It did not take long for the introduction of European cultures, technology and diseases to prompt an end to the Mississauga's way of life.

The fertile agricultural land of the Credit River valley attracted settlers to the area which was to become Mississauga. Much as it does today - world politics and immigration created a demand for land. This prompted the European settlement of the "Home District" out of which "Toronto Township", and later Mississauga, was formed. In 1806, the British government purchased land in the "Mississauga Tract", an area extending from Burlington Bay to the Etobicoke Creek, from the Mississaugas. In this "First Purchase", the Mississaugas retained some fishing rights and one mile of land on either side of the Credit River.

In 1806, Samuel Wilmot completed the survey of the southern half of Toronto Township, and the area opened up for settlement. Many of Mississauga's earliest settlers were United Empire Loyalists, so called because they received land grants for their loyalty to the British during the American Revolution. Regardless of background, the early settlers shared the challenge of creating communities amid daunting conditions.

With the "Second Purchase", on February 28, 1820, the Mississaugas ceded the remainder of their land and additional settlements established including: Barbertown, Britannia, Burnhamthorpe, Derry West, Elmbank, Malton, Meadowvale Village, Mount Charles, and Streetsville. This area, referred to as Block D, excluded a 200-acre reserve on the northeast bank of the Credit River, about 1/4 mile north of Port Credit. The proceeds of any sale or surrender of lands in this Block were intended to go toward the provision of some buildings and some religious and educational instruction. Until this time, the Mississaugas had been a hunting and gathering people. By the 1820s, they had adopted a more settled, agricultural lifestyle.

In 1826, after petitions from Rev. Peter Jones to government officials, the Mississaugas began building a village which was called the "Credit Mission." It is not clear why this village was located on the south bank of the River, rather than on the north, the location of the reserve they had retained. Numbering only about 260 by this time, the Mississaugas petitioned frequently, between 1833 and 1847, for rights to land in Block D. In 1847, the Mississaugas relocated to a reserve in the Grand River Valley near present-day Hagersville. An historic plaque outside the gates of the Mississauga Golf Club is the only visible reminder of the Mississaugas' settlement.

By 1820, the New Survey had been completed and the northern part of Toronto Township was now fully open to new immigrants fleeing a variety of circumstances such as war, famine, overpopulation, and economic depression, to seek opportunities in Upper Canada, as Ontario was then known.

In 1873, in light of the continued growth seen in this area much as a result of the many railway lines passing through the township which spurred on industry, the Toronto Township Council was formed to oversee the affairs of the various villages that were unincorporated at that time. The Council's responsibilities included road maintenance, the establishment of a police force, and mail delivery service. Except for small villages, some grist mills and brickworks served by rail lines, most of present-day Mississauga was agricultural land, including fruit growing orchards through much of the 19th and first half of the 20th century. Toronto residents would travel to the township to pick fruits and garden vegetables.

Cottages were constructed along Lake Ontario in the 1920s as weekend getaway houses for weary city dwellers.

Malton Airport opened in 1937, which would become Canada's busiest, Toronto Pearson International Airport.

The Queen Elizabeth Way highway, one of the first controlled access highways in the world opened to Hamilton and later Niagara in 1939. The first prototypical suburban developments occurred around the same time, in the area of the Dixie Road and the QEW. Development in general moved north and west from there over time and around established towns. Large scale developments such as in Meadowvale and Erin Mills sprung up in the 1960s and 70s.

With the exception of Port Credit and Streetsville, the township settlements of Lakeview, Cooksville, Lorne Park, Clarkson, Erindale, Sheridan, Dixie, Meadowvale Village, and Malton were amalgamated by a somewhat unpopular provincial decree in 1968 to form the Town of Mississauga. The town name was chosen by plebiscite over "Sheridan". Political will, as well as a belief that a larger city would be a hegemony in Peel County, kept Port Credit and Streetsville as independent island towns encircled by the Town of Mississauga. In 1974, both were annexed by Mississauga when it reincorporated as a city. That year, the sprawling Square One shopping centre opened, which has since expanded many times its original size.

On November 10, 1979, a 106-car freight train derailed while carrying explosive and poisonous chemicals just north of the intersection of Mavis Road and Dundas in Mississauga. The resulting fire was allowed to burn itself out, but a ruptured chlorine tank was the main cause for concern. With the possibility of a deadly cloud of chlorine gas spreading through suburban Mississauga, 218,000 people were evacuated. Within a few days Mississauga was practically a ghost town. Later when the mess had been cleared and the danger neutralized residents were allowed to return to their homes. At the time, it was the largest peacetime evacuation in North American history. Due to the speed and efficiency in which it was conducted, many cities later studied and modeled their own emergency plans after Mississauga's. For many years afterwards, the name "Mississauga" was to Canadians associated with a major rail disaster.

North American telephone customers placing calls to Mississauga (and other post 1970 Ontario cities) may not recognize the charge details on their billings, as Bell Canada continues to use the former community names, rather than "Mississauga", to identify exchanges in the city: Clarkson, Cooksville, Malton, Port Credit, Streetsville.

In 2006, an international architectural design competition was held for a 50 storey condominium tower that is intended to be a landmark for the city. The winning design, named Absolute World, by Chinese architect Yansong Ma of the MAD firm, is a bold, curvaceous tower that was dubbed the "Marilyn Monroe" for its supposed sexiness, and has received plaudits from urban architecture critics such as Christopher Hume of the Toronto Star. The building is currently scheduled to be finished by 2010.