The area around Regina was utilized for thousands of years before any permanent settlement existed.  The tribes of First Nations peoples used it as a meeting and gathering place.  A noteworthy feature was a giant pile of bison bones along the banks of a creek, which lead to the place being referred to by the Cree people as "Oscana", or "pile of bones".

In spite of being in the middle of a treeless grassland with few natural sources of water other than the creek, the site was chosen as the capital city of the Northwest Territories. Edgar Dewdney, the lieutenant-governor of the North-West Territories, had selected it out of self-interest; he owned land next to the future route of the Canadian Pacific Railway line where it crossed the creek. Despite this obvious conflict of interest, responsible government had not been established yet, so there were few means of challenging such decisions. Amongst the misgivings and mockery of many political pundits, the settlement was estabilshed in 1882, and was aptly named "Pile-of-Bones".

The village was renamed "Regina" after Princess Louise suggested the name in honour of her mother, Queen Victoria.  Regina is Latin for "queen", which gives rise to the city being referred to as the "Queen City".  To ensure a steady water supply, the creek was dammed to form a reservoir.  The new lake and creek would both be named Wascana, an anglicized form of the Cree "Oscana".

Regina gained notoriety in 1885 during the Northwest Rebellion.  After the final defeat of Metis forces at the Battle of Batoche, the rebellion's leader, Louis Riel, was tried and executed in Regina. Since 1967, a dramatic re-enactment of the trial is staged every summer, with dialogue drawn from the actual courtroom transcripts.

Regina was incorporated as a city on June 19, 1903 and was proclaimed the capital of the province of Saskatchewan on May 23, 1906 by the first provincial government, led by Premier Walter Scott.

 Other significant events in Regina's history include:

  • June 30 1912: A tornado destroyed much of the downtown area, killing 28 people and injuring hundreds. The Regina Cyclone remains Canada's deadliest tornado.
  • 1931: Wascana Lake is drained, enlarged and deepened as a make-work project during the Great Depression.  Over 2000 men laboured by hand, shovelling and removing over 90,000 cubic metres of earth.  Two new islands were built as part of this project.  The new lake would become the centrepiece of Wascana Centre , now 930 hectares (2300 acres) in size and one of North America's largest urban parks.
  • 1933: The Regina Manifesto, the programme of the socialist Co-operative Commonwealth Federation party, is published.  The CCF (today's New Democratic Party or NDP) would form government in 1944.
  • July 1, 1935: Participants of the On-To-Ottawa trek, a protest against conditons in government work relief camps, fought with police in a battle that left one policeman dead and 39 people injured.  The event would become known as the Regina Riot, and would help topple the federal Conservative government of Prime Minister R.B. Bennett.
  • 1962: Doctors go on strike for two weeks to protest the introduction of Medicare, universal state-run health insurance.