Wilkie began his professional career on Capitol Hill as Counsel to Senator Jesse Helms, and later served as legislative director for Representative David Funderburk. He was assigned to the Committee on International Relations and the Commission on Security and Cooperation in Europe. In 1997, he began service as counsel and advisor on international security affairs to Senate Majority Leader Trent Lott, remaining in that office until 2003. From 2003 to 2005, in the Bush administration, Wilkie was special assistant to the President for national security affairs and a senior director of the National Security Council, where he was a senior policy advisor to then-National Security Advisor Condoleezza Rice as well as her successor, Stephen Hadley. Wilkie developed strategic planning for the implementation of the Moscow Treaty, the Millennium Challenge Account, Iraqi Reconstruction and NATO Expansion. In 2009, Secretary of Defense Robert Gates awarded him the Defense Distinguished Public Service Medal, the highest civilian award of the Department. In 2007, while serving as assistant secretary of defense for legislative affairs, Wilkie authored a memo outlining guidelines that restricted congressional testimony to high-ranking officers and civilians appointed by the president. Critics of the guidelines argued that they could impede investigations of the Iraq War, and that the Pentagon had no authority to set the rules. From 2010 to 2015, Wilkie was Vice President for Strategic Programs for CH2M Hill, one of the largest program management and engineering firms in the world. He worked on advising assignments and program management. This involved working with the summer Olympics in London in 2012, as he helped reform the United Kingdom's Defense Supply and Logistics System. From 2015 to 2017, Wilkie was a senior advisor to U.S. Senator Thom Tillis. Wilkie was nominated to be Under Secretary of Defense for Personnel and Readiness by President Donald Trump in July 2017. This nomination was confirmed by the Senate on November 16, 2017. On March 28, 2018, President Trump announced via Twitter that Wilkie would serve as interim Secretary of Veterans Affairs until the Senate confirmed a successor. On May 18, 2018, following the withdrawn nomination of Ronny Jackson, Trump announced that he was nominating Wilkie to hold the Veterans Affairs position full-time. On July 23, 2018, Wilkie was confirmed by the Senate as the next Secretary of Veterans Affairs, by an 86–9 vote. He was sworn in on July 30, 2018. In 2019, he was named fifty-second among the 100 Most Influential People in Healthcare by Modern Healthcare. On March 2, 2020, the office of Vice President Mike Pence announced Wilkie's addition to White House Coronavirus Task Force.
Wilkie said Confederate President Jefferson Davis was a "martyr to 'The Lost Cause'" and an "exceptional man in an exceptional age" in a 1995 speech at the US Capitol. Wilkie also spoke about Robert E. Lee to the Sons of Confederate Veterans at a pro-Confederate event in 2009. He also called abolitionists who opposed slavery "radical", "mendacious", and "enemies of liberty", and stated that the Confederate "cause was honorable," while also condemning slavery as "a stain on our story as it is a stain on every civilization in history". Wilkie is a former member of the SCV. During Wilkie's confirmation hearings, he gave inaccurate answers to Senators in claiming that he had not spoken to Confederate groups in a much longer time than he really had. In sworn statements to the Senate as part of the nomination questionnaire, he failed to include his membership in the Confederate Memorial Committee and omitted his event speeches from responses asking for details on them.
