[3] Augustus Jones, who surveyed the area for the Government of Upper Canada in 1791, states that the native (Mississauga Anishinaabek) name for the stream was Sin-qua-trik-de-que-onk, meaning "pine wood on side".

[10] Projectile points of "Hi-Lo" style have been discovered at four Late Paleo-Indian (10000-7000 BCE) sites in the Duffins Creek watershed.

At the end of the Last Glacial Period, the Duffins Creek met Lake Ontario at a point located 10-20 m below the present surface level.

[11] Scattered remains of chert (flint) tools and flakes have been discovered at several inland sites dated to the Archaic period (7000 BCE-1000 BCE).

[12] Several sites dated to the early and middle Woodland period (1000 BCE-700 CE) exist along the Duffins Creek, but not much research has been done on them.

The Iroquois Seneca people established river-side villages in nearby areas, such as Ganatsekwyagon on Rouge and Teiaiagon on Humber.

[15] However, the Duffins Creek was not as attractive for building a settlement, because a sand bar at its mouth prevented boats from entering it.

[9] When the Europeans arrived in present-day Ajax, at least one Ojibwe family resided in area, as attested by Arthur Field.

Pickering Village and Stoufville, where several mills had earlier been established and which were now accessible by railway, emerged as the major population centres of the area.

[19] The headwaters of the Duffins Creek are located in the Oak Ridges Moraine area,[20] within the boundaries of Uxbridge, Pickering, Markham, and Whitchurch-Stouffville.