Mokoena, sent off in the second half for two yellow card offences, put Blackburn on their way in the 28th minute with his first goal for the club.
Stephen Warnock's cross was headed on by Morten Gamst Pedersen, before dropping into the path of Mokoena who found the bottom corner with a first-time left-foot shot.
Benni McCarthy had the ball in the net minutes later only to be ruled out on an offside verdict and early in the second half a glorious chip from David Bentley beat Nicky Weaver, before bouncing back to safety off the crossbar.
Struggling City had hardly mustered an attack worthy of the name until twice in three minutes Bernardo Corradi managed to force an equaliser. But on both occasions his shots flashed wide.
Blackburn were coasting to a straightforward victory until South African midfielder Mokoena, who had earlier been booked for a foul, dragged down Corradi and saw red.
Cheered on by 7,000 visiting supporters, City attempted to bring an attacking threat to their play, but Brad Friedel's goal rarely came under pressure.
The outstanding Blackburn back four easily coped with being a man down and City's only effort was a poor one, Darius Vassell shooting wide when he really should have hit the target.
Rovers ensured their place in the last four with a quality goal involving two substitutes.
Jason Roberts and Sergio Peter linked superbly down the left for the on rushing Derbyshire to tap home his first goal at Ewood Park.
It was no more than the youngster deserved. He had scored in previous rounds at Everton and Luton and, along with McCarthy, really took the challenge to City.
There was little to comfort Pearce in the visitors' performance.
The shortage of goals remains a key problem and in Corradi and Vassell they don't seem to have the required punch for this level.