His father (CEO of State Planters Bank, later part of Crestar Bank) joined with Norfolk and Western Railroad CEO Stuart Saunders and Richmond School Board President (and later Supreme Court Justice) Lewis F. Powell and others to support Governor J. Lindsay Almond when he decided to break with the Byrd Organization and adhere to the decisions of the Virginia Supreme Court and a three judge federal panel on January 19, 1959, which declared certain new laws designed to maintain segregation unconstitutional.

He graduated with honors from Yale with a Bachelor of Arts degree in 1967, then published his first book, Harry Byrd and The Changing Face of Virginia Politics, 1945–1966 (1968)[2] Wilkinson enlisted in the United States Army in 1968 and served until 1969.

[10] On November 10, 1983, as Wilkinson briefly returned to teach at the University of Virginia School of Law as a full professor, President Ronald Reagan nominated him to the United States Court of Appeals for the Fourth Circuit seat vacated by Judge John D. Butzner Jr., who retired.

[10] From 1996 to 2003, Wilkinson served as the court's chief judge, during which time he wrote and published his fourth book, One Nation Indivisible: How Ethnic Separatism Threatens America (1997).

[11] In 2003, Judge Wilkinson wrote the majority opinion upholding the right of the United States government to detain Yaser Esam Hamdi indefinitely without access to counsel or a court.

With the announcement of Chief Justice Rehnquist's illness in the fall of 2004, NPR reported Wilkinson was on the short list as a potential Bush nominee to the Supreme Court.

In his concurrence, he voiced a strong opposition to the practice of partial-birth abortions: "The fact is that we—civilized people—are retreating to the haven of our Constitution to justify dismembering a partly born child and crushing its skull.

[17] In 2016, Wilkinson dissented when Judge G. Steven Agee found that sectarian prayers offered by Rowan County, North Carolina commissioners at their meetings did not violate the Establishment Clause of the United States Constitution.

In March 2018, Wilkinson wrote a dissent when the circuit denied en banc rehearing to a divided panel's conclusion that the Bladensburg Peace Cross memorial from World War I now violated the Constitution's Establishment Clause.

[24] In August 2018, Wilkinson wrote for the panel majority when it found that the Constitution's Eighth Amendment did not prevent Virginia from criminally prohibiting those it identified as "habitual drunkards" from possessing alcohol.