Chris Barclay rushed 10 times for 50 yards and two touchdowns before leaving early in the second quarter with the game in hand.
Barclay's second TD came two plays after Jyles Tucker's interception, one of three turnovers for the Aggies (1-2).
Marshall Glen completed 3-of-8 passes for 25 yards for the Aggies with one lost fumble before suffering a dislocated shoulder while trying to make a tackle on Tucker's interception return.
With A&T's backup Rico Watkins unavailable with a broken foot, third-stringer Brian Moye was called in. On his second series, Watkins threw an interception that Marcus McGruder returned 25 yards for a touchdown to make it 35-0.
Andrews' third TD on the first drive of the second half made it 42-0 as Wake enjoyed its most lopsided win since a 47-3 victory over UAB in 1999.
Cory Randolph was 2-of-4 for 19 yards and rushed twice for six yards before Ben Mauck took over early in the second quarter.
A&T, playing a I-A school for the first time, had 221 total yards.
Carlos Davalos' 28-yard field goal with 10:37 left in the game prevented Wake's first shutout since a 31-0 win over North Carolina in 2002.
Moye was 9-of-18 for seven yards while Quante Speight rushed for 67 yards, all in the second half.
The game marked the first meeting between the schools, separated only by about 30 miles. It was also the first football game between an active Atlantic Coast Conference member and a historically black school.