The area was first inhabited by native peoples who used the Mattawa River as an important transportation corridor for many centuries. In 1610, Étienne Brûlé and in 1615, Samuel de Champlain were the first Europeans to travel through the Mattawa area. For some 200 years thereafter, it was a link in the important water route leading from Montreal west to Lake Superior. Canoes travelling west up the Ottawa turned left at "the Forks" (the mouth of the Mattawa) to enter the "Petite Rivière" ("Small River", as compared to the Ottawa), before continuing on to Lake Nipissing.
Other notable travellers who passed by Mattawa include: Jean Nicolet in 1620, Jean de Brébeuf in 1626, Gabriel Lallemant in 1648, Pierre-Esprit Radisson and Médard des Groseilliers in 1658, La Verendrye in 1731, Alexander MacKenzie in 1794, and David Thompson in 1812
Mattawa House was established by the Northwest Company in 1784. In the 1820s and 1830s, the Hudson's Bay Company (after it had merged with the Northwest Company) sent canoe brigades from their Fort Coulonge Post to the Mattawa River junction in order to trade furs. In 1837, a permanent post was established, but was moved to a new site in the centre of present-day Mattawa in 1843. It was subordinate to Fort Témiscamingue and Fort Coulonge, but after the arrival of the telegraph in 1871 and the railroad in 1880, it became the headquarters of the Timiskaming District. As the fur trade diminished and the population grew, the post became a general store, trading merchandise to supply lumbermen. It closed in the early 20th century (1908 or 1912, depending on source).