Arsenal struggled against fifth-round triumph over Mansfield Town in the last round of this competition and enter the clash on the back of the EFL Cup final to Manchester City.
Arteta's side can still match City and Manchester United's feat of completing a treble of Champions League, Premier League and FA Cup this season as they seek a path to the Semi Final.
Southampton are one of two teams outside of the Premier League that are still in the competition, alongside Port Vale as they fight to make history this weekend.
Why did Arsenal recall so many players?
Arteta first opened up on withdrawing a number of players from international duty over the past week as he protects his players from injury.
"We have very good relationship and communication with most of the national teams - certainly with (England manager) Thomas (Tuchel) too.
"We have been extremely supportive all the time. When you have to communicate the state of every player, we are always honest and a medical decision had to be made. That was clear what the conclusion was.
"Players are desperate to play for their nation. I know how important it is to them. We are fully supportive of that and when we can do it, we do it."
Who is available for Arsenal?
After so many players returned to North London, reports are unclear as to which players are injured and which are being rested. Questions turned to team news and Arteta remained elusive as he backed away from revealing who can start against Southampton.
"You will see. I will let you do the speculation. You can judge afterwards.
"We are in a position right now where we need to make the strongest line-up we possibly can to win every competition. We are two or three games away from the FA Cup and we know how important that competition is for us."