The first inhabitants of what is now called Madawaska County were the Maliseet or Wolastoqiyik, who occupied and used the land along the Saint John River Valley north to the St. Lawrence River and south to the Penobscot River.

There is debate concerning the true origin of the word "Madawaska".

The area was the focus of the bloodless Aroostook War, a border dispute led by businessman and political activist John Baker.

The earliest settlers of the Upper Saint John River Valley have been clearly verified, with census results of the Madawaska region taken in 1820 showing where most families had originated from Quebec.

[8] Highways and numbered routes that run through the county, including external routes that start or finish at the county limits:[11]