After moving to Franklin County, Virginia, in 1802, Burwell became involved in politics and thrice won election to represent Franklin County in the Virginia House of Delegates, serving in that part time position from 1804 to 1806 alongside Henry T. Callaway before being succeeded by John Callaway after his election to the U.S.

[2] During that period, Meriwether Lewis retired as President Thomas Jefferson's private secretary to make his famous westward expedition, and Burwell would succeed him and move to Washington, D.C. Burwell then sought election to the U.S. House of Representatives, and was elected as a Democratic-Republican to the United States House of Representatives to fill a vacancy.

Ten times (with gaps), Bedford County voters elected William M. Burwell as one of their two representatives in the Virginia House of Delegates.

The younger Burwell secured subsidies for the Virginia and Tennessee Railroad, which passed through his Avenel farm in the county seat (then called Liberty, but which would expand after the American Civil War onto that property).

His eldest, Letitia M. Burwell (1831–1905), wrote two books supporting the Lost Cause, the most famous being A Girl's Life in Virginia Before the War.