McDonald was appointed to serve in a number of prominent political positions including a superintendent overseeing the construction of the Northwestern Turnpike and a commissioner representing Virginia in its boundary dispute with Maryland.

[1] In October 1814, McDonald's father, a United States Army major, died following a forced march near Batavia, New York, during operations related to the War of 1812.

[12] McDonald's athletic physique, confidence, and fearlessness earned him the sobriquet of "Big Knife" from various Native American tribes of the Missouri Territory.

[9][17] McDonald and his wife resided in a log dwelling located on Lot 26 at the intersection of West Main and North Bolton Streets in Romney.

[9] McDonald became well known in the legal profession[18] and continued to engage in and grow his lucrative law practice for the succeeding 17 years, which allowed him to amass and invest in large tracts of land in the American West.

[20] McDonald also proposed building the turnpike through the garden of the Clerk of the Hampshire County Court, John Baker White.

[20] This rerouting remains evident today in the curve of Main Street in Romney in front of White's residence, now known as "Liberty Hall.

[24] In keeping with the Virginia law requiring citizens to own a particular amount of land in order to exercise their right of suffrage, McDonald transferred tracts of land of the requisite amount of acres to young men belonging to the Whig Party to enable their vote in elections that McDonald was particularly interested in the outcome of.

[9][25][26] He sold the log dwelling in Romney to William Davis in 1849,[9] although McDonald and his family continued to reside in Romney at least until 1850[27] In 1853,[28] McDonald and his family relocated to "Wind Lea" in Paddy Town (now known as Keyser), a settlement along the North Branch Potomac River and Baltimore and Ohio Railroad in western Hampshire County (now Mineral County).

[31] McDonald communicated his discovery to the Virginia General Assembly in the Winter of 1859, after which the legislature authorized him to travel to England in order to conduct further research for boundary records in the archives of the State Paper Office.

Prior to the outbreak of the American Civil War, McDonald sympathized with the secessionist cause, but his feelings softened during his trip abroad, where he found a "united republic" preferable to a cluster of sovereign states like Europe.

[34] A company that included Captain Turner Ashby was assigned to McDonald, who divided it into small detachments that were sent out on scouting expeditions as far south as Washington City.

[35] In June 1861, McDonald and his cavalry occupied Romney,[36] but were defeated by Union Army forces in their defense of the town by July.

[37] McDonald's 7th Virginia Cavalry fought a Union column under the command of Colonel James Cantwell in the Skirmish at Hanging Rock Pass on September 24, 1861.

[38] On the evening of September 23, 1861, McDonald received information that Union Army forces planned an attempt to pass through the gap at Hanging Rocks early the next morning.

[35] Following the aftermath of Major General Stonewall Jackson's Romney Expedition, McDonald traveled to Richmond, where he served as an advisor to the Confederate States War Department.

[26][30] In July 1864, while McDonald was residing in Lexington, he was arrested along with his son Harry by Union Army General David Hunter, who had previously caused damage to his property "Hawthorne" in Winchester.

[40] Harry escaped one or two days later, but McDonald remained captive and was hastily "tied and dragged" to the Maryland state line.

[40] McDonald's funeral service was held the evening after his death on December 2 at St. Paul's Episcopal Church and he was interred with full military honors at Hollywood Cemetery in Richmond.