Rashford and Sancho have not featured in recent England squads
The Three Lions are five months away from heading to Qatar, with September's two Nations League fixtures all that remain after facing Hungary on Tuesday.
Harry Maguire is the only Manchester United player involved in the England set-up this month.
Luke Shaw has been regaining fitness while Rashford and Sancho missed out.
Southgate last month said the pair still have time to work their way into his World Cup plans, but he has now admitted it is an uphill battle for them to seal their place.
Asked if United players may be fresher without the Champions League to contend with next season, the England boss said: "We've only got one with us. They've got a lot to do to get back in the squad.
"Well, look, I think the lower the load then of course the less likely for injuries and the hope that players can be that little bit sharper but there's no way of knowing.
"Some players are at their best when they're in a rhythm of playing and you talk to some of our lads now and they want to play every game because that's how they feel they get to their best level.
"Others need the breaks, they need longer recovery between the matches to be at their best."
Rashford and Sancho were not picked for March's internationals and overlooked again for June's four Nations League matches.
Rashford has not played for England since missing his penalty in last summer's European Championship final defeat to Italy, having withdrawn from November's squad to focus on regaining fitness after shoulder surgery.
Departing midfielder Jesse Lingard and goalkeeper Dean Henderson are other United players to have dropped off the radar following a challenging campaign for the Old Trafford club.
Southgate hopes the Premier League keeps England's World Cup preparations in mind when deciding next season's fixtures.
It has been reported the Football Association submitted a formal request to the league requesting that no match between the so-called big six takes place on the weekend of 12-13 November.
England are scheduled to fly to Qatar on 15 November before their opening match against Iran six days later, before completing Group B against the United States and Wales.
The Premier League reveals its fixture schedule for the 2022-23 season on Thursday.
"We have asked the Premier League to have a think about things but we also understand that they've got a lot of [things to consider]," Southgate said.
-- Courtesy of BBC Sport