[5] The Ohio Company of Virginia petitioned the British King for 500,000 acres of land in the Ohio River Valley in 1747, but the first settlers to this area, in what later became known as West Virginia's Northern Panhandle, were brothers Jonathan, Israel and Friend Cox.

In 1788 Charles Prather purchased 481 acres from Friend Cox's heir, John Cox; by that year's end Alexander Wells, formerly of Baltimore, Maryland and later of Cross Creek Township, Pennsylvania, established a trading post (together with his Baltimore cousin Richard Owings).

In 1791 the Ohio County Court incorporated the town around the post as "Charlestown" (after Prather's first name).

Across the Appalachian Continental Divide to the east in Jefferson County, another Charlestown had previously been incorporated (it is now known as Charles Town).

Addressing this confusion, the Virginia General Assembly on December 28, 1816, changed the Brooke county seat's name from "Charlestown" to Wellsburg, supposedly to honor Charles Wells, Prather's son-in-law.

[7] The first Masonic Lodge west of the Allegheny Mountains was established in Wellsburg on March 4, 1799.

[8] The first glass factory in Wellsburg was built in 1813, taking advantage of the relatively easy transportation on the Ohio River.

When the National Road was built about five years later, its first crossing of the Ohio River was via a ferry further west.

[9] In 1863, West Virginia's counties were divided into civil townships, with the intention of encouraging local government.

This proved impractical in the heavily rural state, and in 1872 the townships were converted into magisterial districts.

The highest point of elevation in Brooke County is approximately 1372 ft. and located about 1.5 miles south of Franklin.

[19] In terms of ancestry, 21.5% were German, 17.5% were Irish, 16.4% were Italian, 11.5% were English, 7.2% were American, 5.9% were Scotch-Irish, and 5.7% were Polish.

The Brooke County Commissioners in 2022 are President AJ Thomas, Tim Ennis, and Stacey Wise.

Vacancies occurring in unexpired terms can be filled by a respective Circuit Court Judge.

Brooke County currently has two magistrates: Robin Snyder and Danielle Diserio.

[25] Abutting free states Ohio and Pennsylvania, and with a largely German-American culture unlike any other part of antebellum Virginia,[26] Brooke County and the rest of the Northern Panhandle were central to the vanguard who made West Virginia a new state during the Civil War.

[27] For the next six and a half decades the county, aided by its association with Pennsylvania's powerful ironmonger-led Republican machines, voted solidly Republican to the point of supporting William Howard Taft during the disastrously divided 1912 election.