After brushing aside Rotherham United 3-1 at Goodison Park on Wednesday, the Toffees will now welcome Mark Hughes’ men, who are currently 17th in the Premier League.
The tie will take place during the week commencing September 24, though is likely to be played on Wednesday, September 26, given Everton face Arsenal in the Premier League on the previous Sunday, September 23.
It will offer the Saints the chance for revenge over the Blues after they were beaten 2-1 at Goodison in the Premier League on August 18. Southampton won 1-0 at Brighton and Hove Albion to make it to the third round.
Their run in the tournament last season lasted until the fourth round, when they were beaten 2-1 by Chelsea at Stamford Bridge in October.