Gus Poyet intends to give the likes of Emmanuele Giaccherini and Ignacio Scocco an opportunity on Saturday despite the extra rest afforded by a midweek postponement.
The Black Cats' Premier League trip to Manchester City on Wednesday was postponed due to inclement weather, allowing Poyet's star men an extra break ahead of the last-16 tie but, despite the unexpected rest, the Uruguayan intends to stick to his original plan and make several changes.
"I was looking forward to giving a few players opportunities and that will not change," he told The Sunderland Echo. "We have a few players who need to play and deserve to play but, for different reasons, they haven't been able to.
"I'm talking about players like [Emanuele] Giaccherini and [Ignacio] Scocco. They both need minutes so we're going to use that game for this but it will all be first-team players. We will not be taking the game lightly. I hope that we win it so we don't have to have a replay."
Sunderland, which will be without the suspended Wes Brown, has had a relatively straightforward run to the fifth round, with home victories over Carlisle United and Kidderminster Harriers to date, and the team has enjoyed even greater success in the Capital One Cup, with Poyet's men due to take on Manchester City in the final at Wembley on March 2.
The Wearsiders remain in trouble in the league, however, sitting 18th, albeit with a game in hand over most of their rivals.
Southampton, on the other hand, is enjoying a fine season and sits eighth in the Premier League table. Mauricio Pochettino's men come into the game on the back of an eight-match unbeaten run in all competitions, including wins over Championship outfits Burnley and Yeovil Town in the third and fourth rounds of the FA Cup.
The two sides met in the league in January, with Sunderland coming from two goals down to claim a 2-2 draw, and the Saints' assistant manager, Jesus Perez, says that his side has learned its lesson as the club looks to reach the last eight of the competition for the first time in nine years.
"We know Sunderland very well," he told reporters. "This will be the fourth time we've met them [since Pochettino took charge] but, when you are playing a lot of competitions, that's always a possibility.
"We are ready to face them. We have learned from every game against them. We review and analyze every game to determine how we have to improve in case we have to repeat situations."