Gus Poyet's side sit three points above the drop zone in the top flight after their 3-2 defeat to Manchester City on Thursday, but the tables will turn on Sunday as they become the favourites for the cup clash.
However, a hectic period of games in December has only produced one win – against bitter rivals Newcastle United – and the injuries are beginning to build up.
Lee Cattermole (groin) and Santiago Vergini (knock) are the latest to be ruled out of this weekend's match leaving Poyet with a decision to make.
Ideally the Uruguayan – who was assistant at Leeds for 12 months from October 2006 – would like to give some of his squad a rest ahead of league matches against Liverpool and Tottenham, but he concedes that may not be possible.
"It's not going to be an experiment or playing a weakened side," Poyet told a media conference on Friday. "I'm going to try to change not too many.
"But when I mean not too many, I mean I’m going to try to play the best team I can play from the first-team squad.
"There's players who’ve been playing with some pain and we need to be careful. We need to be careful because we don’t want to lose any players for next week.
"But we want to put the best team out that we can."
The match is the first meeting in the competition between the sides since the 1973 final, when then second division Sunderland beat Don Revie's Leeds 1-0 thanks to Ian Porterfield's strike.
The tables are very much reversed in 2014, though, with Leeds staring at relegation from the Championship after a dreadful run of form.
A 2-0 defeat to Derby County on Tuesday left Neil Redfearn's side one point above the bottom three in the second tier, with only one win in their last seven matches.
Redfearn's future at the club came under scrutiny after that defeat – their fourth in five – but he will lead the side at the Stadium of Light.
Leeds have only won once on their travels in all competitions this season, but the 49-year-old head coach hopes they can shrug off their league woes and play without any pressure.
"It's a good game to look forward to us," he told the Yorkshire Evening Post. "We've got to be positive."
The visitors can take solace from their previous exploits against higher-ranked opposition, having knocked Manchester United out in the third round in 2010.
Jermaine Beckford scored the winning goal that day, while Luke Varney and Ross McCormack booked them a fifth-round place at the expense of Tottenham two seasons ago.
This weekend Leeds' hopes sit on the shoulders of top scorer Mirco Antenucci, who has eight goals to his name in 21 appearances.
