McDonald served as an assistant professor of chemistry at the institute under Stonewall Jackson and continued to teach intermittently throughout the American Civil War.

Following the war in 1865, McDonald returned to the Virginia Military Institute where he was appointed a professor with the rank of colonel, instructing and serving as chair of the subjects of chemistry, geology, mineralogy, and metallurgy.

[5] The McDonald's raised nine children—five sons and four daughters—in a log dwelling in Romney owned by Leacy Anne's father, William Naylor.

[6] The structure, currently known as the Davis History House, remains standing on its original site at the corner of Main and Bolton Streets and serves as a museum maintained by the Hampshire County Public Library.

[9][10] Following the death of McDonald's mother Leacy Anne, his father sold the Naylor family's log dwelling in 1849 and moved to Hannibal, Missouri, in the 1850s only to return to Virginia a few years later upon marrying his second wife, Cornelia Peake.

[15][16] During the war, McDonald and other former cadets returned to the Virginia Military Institute to instruct pupils while on parole or recuperating from injuries.

[6] His father was one of the first Hampshire County residents to volunteer to fight for the Confederacy in 1861 and was commissioned as a colonel in command of the 7th Virginia Cavalry Regiment.

[20] During the 1867–1868 academic year, McDonald's chair was further subdivided as new lecture halls were being completed within the restored barracks; he retained the subjects of mineralogy, geology, and metallurgy.

[21] His colleagues among the faculty included Superintendent Francis Henney Smith and professors Matthew Fontaine Maury, Scott Shipp, John Mercer Brooke, and George Washington Custis Lee.

[12] This ladder enabled salmon and other migrating fish species to ascend the rapids of watercourses, thus increasing the extent of their spawning grounds.

[13] McDonald continued to instruct at the Virginia Military Institute until 1879, when Spencer Fullerton Baird offered him a position with the United States Commission of Fish and Fisheries.

[1] He continued in that capacity until January 1888 when President Grover Cleveland appointed him to replace Dr. George Brown Goode as the Commissioner of Fish and Fisheries.

[18] His appointment was widely recognized as an "excellent" choice because of the breadth of his experience, his organizational and leadership abilities, and his sense of duty and responsibility to the American people.

[24] McDonald believed the first step toward building "a comprehensive knowledge of the conditions of greatest productiveness" of American fisheries was to understand the primary food supply of fish, which he termed "aquatic pastorage.

[12][13][18] The hatching jar apparatus enabled a "vast extension" of the propagation of shad accomplished in the 1880s and 1890s and rendered the work of the Fish Commission commercially successful.

[12][13] By 1890, McDonald was residing at 1514 R Street, Northwest in what is now known as the Logan Circle neighborhood of Washington, D.C.[3] After suffering from tuberculosis for several months,[12][22] He traveled to the Adirondack Mountains with his wife in the early summer of 1895 seeking to benefit from the region's "health-giving air".

[2][12][22] McDonald was interred on September 3 next to his daughter Nannie in Lot 432 East at Oak Hill Cemetery in Washington's Georgetown neighborhood.

"[12] Marcus Benjamin, in his remembrance of McDonald for the District of Columbia Sons of the American Revolution, remarked: "His articles and reports on the fishing industries of the world are of great interest and his efforts in behalf of the oyster have resulted in much good.

"[18] Benjamin further stated, "McDonald's bearing was always kind and generous to a fault, and his tread and manner carried for him a remembrance of his long line of military ancestry.

[33] In 1890, McDonald applied for and acquired membership in the National Society of the Sons of the American Revolution through the organization's District of Columbia branch.