Jefferson County was originally the home of the Kanza Indian tribe where buffalo roamed. In 1827, Major Daniel M. Boone, son of famous Kentucky pioneer Daniel Boone, established Kansas' first settlement in Jefferson County. The United States Government established a reservation there for the Delaware Indians, who were relocated from Indiana and Ohio. The "Old Military Trail" route through the county was used by the Cavalry between Fort Leavenworth and Fort Riley. Jefferson County is named in honor of former President Thomas Jefferson. It was Jefferson who acquired this parcel of land as part of his famous Louisiana Purchase.

Jefferson County is located in the northeastern part of the state, the second county west from the Missouri river and the third south from the Nebraska line. It is bordered on the north by Atchison County, on the east by Leavenworth, on the south by Douglas County, and on the west by Shawnee and Jackson counties.

Jefferson County is home to over 18,000 residents and encompasses 568 square miles or 363,520 acres. The Delaware (formerly the Grasshopper) River enters on the northern border about 4 miles from the west line and flowing south joins the Kansas River at Perry. Big Slough Creek is the main branch of the Delaware. Muddy creek crosses the southwest corner of the county.

Jefferson County is the sight where two major Civil War battles occurred, the Battle of Hickory Point and the Battle of Slough Creek.