With the World Cup set to start in November, Rashford and Sancho are running out of time to book their place on the plane to Qatar after missing out on the last two England squads.
Rashford has lost his England place after experiencing a drop-off in form that resulted in just 13 Premier League starts for Manchester United last term, while Sancho struggled in his first season at Old Trafford, scoring three goals in 29 league games.
Southgate was asked by reporters whether the lack of Champions League football would ease the workload for the out-of-favour Man United players.
The England manager issued a warning in reply: "They've got a lot to do to get back in the squad. We've only got one [Maguire] with us! 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 has featured 46 times for his country, scoring 12 goals in that period, while Sancho has found the net on three occasions across his 23 international appearances.