In 1763, Chief Seckas of the Thames River brought 170 warriors to the siege of Detroit during Pontiac's uprising. The reserve was established in 1819, as part of a treaty by which the Chippewas of the Thames agreed to share 552,000 acres (2,234 km²) of land with the British for an annuity of £600 and the establishment of two reserves, of which reserve no. 42 is the larger. In 1840 the Chippewas reached an agreement with the Munsee-Delaware Nation to share the reserve. The Munsee portion of the reserve became part of the new Munsee-Delaware Nation No. 1 reserve in 1967.
In April 2004, the Chippewas of the Thames First Nation had a registered population of 2221, of whom 876 lived on the reserve. By January 2011, the Nation had a total registered population of 2462, of whom 911 lived on the reserve.