In 1998, Holding left the practice of law to serve as legislative counsel to U.S. Sen. Jesse Helms in Washington. He was employed by Maupin Taylor, a Raleigh law firm, from 2001-2002. Holding joined the U.S. Attorney's office for the Eastern District of North Carolina in 2002, working under Frank Whitney. Under Whitney, the U.S. Attorney's office prosecuted a number of high-profile public corruption cases, including former N.C. Agriculture Commissioner Meg Scott Phipps, former House Speaker Jim Black and former U.S. Rep. Frank Ballance. In June 2006, Bush appointed Whitney to a federal judgeship.

In September 2006, Holding was confirmed by the U.S. Senate as Whitney's replacement. His priorities included increasing child pornography and drug prosecutions. In addition to the prosecutions under Whitney, Holding prosecuted a state judge, a state Senator, a state Representative, and several sheriffs for political corruption. After Barack Obama won the presidency, Holding was asked to remain in office to complete ongoing public corruption investigations.

When Holding left office the average sentence in drug trafficking cases in eastern North Carolina was almost twice the national average. He indicted eight defendants for conspiring to promote terrorist attacks in the United States and abroad and convicted a number of child pornographers, several of whom were sentenced to more than 100 years in prison.

He worked closely with state prosecutors investigating former Governor Mike Easley, who was convicted of a state felony.

After his resignation in 2011, Holding announced his candidacy for Congress. He was endorsed by multiple business and civic leaders, including N.C. Supreme Court Chief Justice I. Beverly Lake and former U.S. Senator Lauch Faircloth.

George and his wife Lucy have four children – three daughters and one son – and are members of Christ Baptist Church in Raleigh.