United take on Chelsea in a quarter-final replay at Stamford Bridge on Easter Monday with a semi-final date with City at Wembley waiting for the winner.
And Smalling is eyeing payback for the final-day heartbreak that saw Roberto Mancini's men claim the Premier League title in May.
"When we saw the draw, it was a definitely the case that the prospect of playing City gives us an extra incentive," said the England international, quoted in the Sunday Mirror.
"It's at Wembley as well, so it would be a massive occasion. But we need to make sure we get past Chelsea, which won't be easy.
"It would be the ultimate revenge to beat City to the Premier League title and knock them out of the FA Cup, especially after last year. It would be so sweet."
The Old Trafford mantra all season has been one of ensuring there is no repeat of last season's disappointment and Smalling is determined to seize his chance if it comes along.
"It's drilled into everybody at the club to use the disappointment of last season," he added. "None of us want that feeling again.
"It was horrible and we had all summer to dwell on it. So, it's nice to be in a position now where we can hopefully make it count.
"Everybody finished last season disappointed, but as soon as the first day of pre-season came about, everybody was firing.
"New players came in and we've shown, with our spirit, that we don't want to experience the same feeling again.
"It's about how you react to disappointments and the manager wanted to see that reaction. If I get my chance, then I'm going to take it."