Benitez said it is "impossible" for players to be at their peak for two matches inside 48 hours and the demands of back-to-back fixtures will colour his selection.
But Chelsea's interim manager admitted he does not have the same luxury as Sir Alex Ferguson, who could name two entirely different sides for Manchester United's fixtures over the Easter weekend.
"We can't do that. The difference between them and us is that they are 15 points ahead (at the top of the Barclays Premier League)," Benitez said.
"It is not an excuse. The reality is that their position in the table gives them an advantage and they are out of the Champions League. Their priority will be the FA Cup.
"We have to pick a very competitive team for Southampton. If we can beat Southampton we will be keeping an eye on (trying to catch) Manchester City."
Chelsea are entering what Benitez described as the defining period of their season, with five matches in the next 13 days including quarter-finals in both the FA Cup and Europa League.
John Terry's improving fitness is a boost for Benitez, who also expects to have Gary Cahill and Ramires fit to face United on Monday lunchtime.
The squad will come into training on Sunday, with those who play against Southampton put through a light recovery session while the rest focus on practice and tactics for the United game.
Benitez must be tempted to start with Demba Ba at the St Mary's Stadium because the Senegal striker has scored three times against Southampton this season since his move to Chelsea.
Ba marked his debut with a double in the FA Cup and then scored in the league at Stamford Bridge before Southampton came from 2-0 down to claim a draw.
"It is not easy to make a decision (on selection) because it is impossible to be fully fit for the second game," Benitez said.
"The day after a game you feel tired, two days after you feel even more tired. That is the reality. The second day will be really tough for everyone.
"All of them they can play (two games in 48 hours) but at what level?
"Sometimes you can do it if you are not 100% but it depends on each position and each player."
If Ba plays against Southampton then Benitez may have to turn to Fernando Torres to face United, which would be a bold call given how the Spaniard has struggled for goals this season.
Benitez said: "Strikers want to score goals but for me it is not just that, it is what they can do for their team."