United face the Tigers at the KCOM Stadium (7.45pm kick-off) just three days on from the 1-0 defeat at home to Blackburn Rovers in the Sky Bet Championship.
But the Magpies boss insists that despite Mike Phelan's men being a top flight side, "anything can happen" in a cup tie as Newcastle bid to make it through to the last four and respond after Saturday's setback in the league.
"We approach every game with confidence, but the main thing is to be sure we don't have over-confidence. In this case, it's a Premier League team, so we know that we will have the right motivation and the concentration to do well," he said.
"They are a Premier League team at the moment, and when you are there, you play at another level with different players. But also my experience in cup competitions is that anything can happen, so we approach the game with belief. If we play well, we can win, if we don't play well, we can lose.
"In terms of the game, it will be a tough game for both. Hopefully that means we will do well. We will see what happens."
Benitez made six changes to his starting line-up for the defeat to Blackburn, and he says he may again elect to shuffle his pack for the midweek tie.
"I am very pragmatic. I approach the game with the same idea. For me, the cup competitions are an opportunity to do well, to progress, but at the same time I know how difficult it is to win something with the level of the teams that you have already in the Premier League," he said.
"We will try to win, try to progress and try to go as far as we can. But you have seen the squad we have - I will not risk players if I think it is not necessary."
Charlie Mulgrew's second half strike condemned Newcastle to defeat at the weekend, ending their nine-game winning streak in the process.
But Benitez says his side have a chance to put things right straight away as they look to seal a semi-final berth.
"From the beginning, we were not doing well. In the first 15 minutes, we were gibing the ball away, and we were not playing with the intensity that we have in other games," he said.
"We started much better in the second half and had three chances that could change everything, but if you see the whole game, we didn't play at the level we were playing at before. We didn't do well, and we have to quickly change.
"The conversation after the game has been about trying to bring all the positives that we have seen during the season, and trying to replicate this and do it in the next game. We have an opportunity tomorrow, so hopefully we can do well."
