Holders Liverpool also rang the changes and came from behind at West Bromwich Albion to win 2-1 thanks to two goals from Nuri Sahin.
Tottenham Hotspur beat Carlisle United 3-0 and their North London rivals Arsenal strutted into the last 16 with a 6-1 drubbing of third tier Coventry City.
"Newcastle had a stronger team than us physically. We played fantastic football and I think we deserved it," United manager Ferguson told Sky Sports.
"Anderson's was a great strike. The second is a great bit of football. Cisse is a terrific player. Our defence handled it well."
Liverpool also fielded a completely different team and fell behind on three minutes when West Brom's Gabriel Tamas finished from close range after a mistake from the visitors' stand-in keeper Brad Jones.
Playmaker Sahin, on loan from Real Madrid, levelled with a speculative shot from distance and struck again late in the second half when he converted Oussama Assaidi's cross at the back post.
Forward Jerome Sinclair became the club's youngest ever player at 16 years and six days when he came on as a second-half substitute.
"It's congratulations to Jerome Sinclair. Our future is bright with the young players. The style and definition of our game is improving all the time," said Liverpool manager Brendan Rodgers whose name was sung Liverpool fans at the final whistle.
"It's great to see the kids playing with confidence. We fully deserved the win. For me it's about talent irrespective of age. We've got a small squad. It's a club where young players are going to get a chance."
