It rises in Knox County at 40°03′30″N 92°15′26″W / 40.05833°N 92.25722°W / 40.05833; -92.25722[2] (northwest of Novelty) and flows southeast and east through Shelby and Marion counties, emptying into the Mississippi River at 39°51′21″N 91°26′41″W / 39.85583°N 91.44472°W / 39.85583; -91.44472[2] between West Quincy and Hannibal.
The North River drainage area is 373 square miles (970 km2), with a median flow of 38 cu ft/s (1.1 m3/s) and a mean flow of 231 cu ft/s (6.5 m3/s) based on 72 years of record at the USGS Palmyra gaging station.
Zebulon Pike identified this river as the Jeffreon in his August 19 journal entry with the spelling "Jauflione", although no distinction other than "The Jauflione is about 30 yards wide at its mouth, and bears from the Mississippi about S.W."
In the same treaty the tribes ceded much of northern Illinois and southern Wisconsin on the east side of the Mississippi.
It derived its current name from its position relative to Palmyra, Missouri.