The United boss questioned the pair for missing Sunday's 3-1 Premier League win at Swansea, saying: "For the team, you have to do anything."
Smalling has a foot injury, while Shaw played in United's Europa League defeat by Fenerbahce on Thursday.
Southgate said there was "obviously something wrong" with both players.
Central defender Smalling, 26, and left-back Shaw, 21, have been left out of the England squad for Friday's 2018 World Cup qualifier against Scotland and next week's friendly against Spain.
Shaw has played six league games this season since returning from a double leg break last September.
Asked by media if the two players were "flaky" characters, Southgate replied: "That wouldn't be my impression.
"Luke I know well and Luke's had a really tough injury. I think very often it's easy to look from the outside or to make judgements on people without knowing them really, really well."
Shaw has played six league games this season since returning from a double leg break last September.
Asked by media if the two players were "flaky" characters, Southgate replied: "That wouldn't be my impression.
"Luke I know well and Luke's had a really tough injury. I think very often it's easy to look from the outside or to make judgements on people without knowing them really, really well."
