The FA Cup quarter-final replay against United comes less than 48 hours after the Barclays Premier League loss against the Saints.
Benitez made seven changes for the trip to St Mary's, no doubt with an eye on Monday's clash with Sir Alex Ferguson's side in mind.
The gamble backfired as goals from Jay Rodriguez and Rickie Lambert earned Southampton the victory, with returning skipper John Terry briefly levelling the scoreline in the first half.
But Benitez reckons the longevity of a Premier League season compared to the cut-and-thrust nature of knockout football means he had to shuffle his pack.
"You have to make decisions and use the squad," he said.
"Southampton is a good team on one level and Manchester United is another team on another level.
"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."
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- Sir Alex Ferguson
- Rickie Lambert