The FA Cup quarter-final replay against United comes less than 48 hours after the Barclays Premier League loss against the Saints.
"You have to make decisions and use the squad," Benitez said.
"In the league, you have more games to play and will be going to the end. In the FA Cup you have one game and you will be out.
"You have to find the balance for players who are playing more games or less games."