Steve Cotterill will be hoping for a cup upset against the Premier League high flyers following their extra time win over Oxford United at the weekend.
Salop's last clash vs the Saints was a 2-0 defeat at St Mary's back in 2010 with Adam Lallana on the scoresheet for the hosts.
Their league fixture with Oxford will now be rearranged.
Meanwhile Wolves will face familiar foes in Crystal Palace at Molineux,
Nuno's men will be looking for a repeat of their 2-0 victory in the league in October.
Goals from Rayan Ait-Nouri and Daniel Podence were enough to take take the spoils.
Aston Villa will be hoping for a repeat of their 7-2 win over Liverpool as Jurgen Klopp's men as they were drawn at home vs the Reds.
A hat-trick from Ollie Watkins, a double for Jack Grealish and a goal each for Ross Barkley and John McGinn provided the shock result of the season to date.
And after registering their first Premier League win of the season,West Brom will be confident of victory as they travel to Blackpool.
Ties will be played over the weekend of January 9/10, and there will be no replays.
Instead, any ties that are level after 90 minutes will go to extra-time and, if necessary, penalties.