The 32-year-old Brazil international was hauled off at half-time after mistakes led to two goals for the visitors.
And manager Erik ten Hag has brought him out of the firing line, replacing him with Christian Eriksen for the 12.30pm kick-off at St Mary's.
Prior to Saturday's game, manager Ten Hag insisted that Casemiro remained an important part of his plans despite the £50m arrival of Manuel Ugarte.
Erik ten Hag has made the decision to drop Casemiro from Man United 's starting XI
'You definitely need him, for sure,' said Ten Hag, revealing that he has discussed with Casemiro about his role. 'Of course I speak with him about the situation.
'Everyone can have a bad day at the office - have you never had a bad day at the office? He [Casemiro] is experienced. I guess it's not the first time he's had to deal with a bad game, so he has to overcome this as well.
'But it's normal in life you have highs and lows. In your life and in the life of a football player, there are many people observing this and who have an opinion on this and you have to deal with this.
'He knows how to deal with it. Nobody's career goes only up, no team's pattern only goes up. Then you have to deal with it then it is about what is the end result.
'I normally do talk to him and in this case I did as well, but players in our club know when you are playing at this level, there is always competition.
'They also know you can only be successful if you have a squad that has cover. You can't have a squad where you only have one player who can cover this you need at least two for each position, sometimes three.
'Then it's about what is the best fit for the team. They have to prove it, that is the key word. They have to take responsibility and win games for the club.'