While the Saints have lost three out of their last four outings, the Magpies are without a top-flight victory in five attempts.
After witnessing his team go four games without scoring in the Premier League, Steve Bruce would have been relieved to see vast improvements made during the 3-2 victory over West Bromwich Albion in the FA Cup.
Nevertheless, as Bruce acknowledged after Tuesday's game, the Magpies have a habit of making things difficult for themselves, regardless of the competition.
While they can now look forward to a date with Manchester City in the quarter-finals, Bruce knows that they must regain their clinical touch in the top flight in order to avoid any kind of a relegation battle.
Newcastle still hold a five-point cushion ahead of the drop zone, although that will soon change if they fail to collect many points from their next five matches, four of which come against potential relegation rivals.
Although Miguel Almiron took his tally in the FA Cup to four against the Baggies, the playmaker is under pressure to contribute more in the Premier League with just two goals and one assist to his name.
Like Saturday's opponents, Southampton also have a number of crucial encounters against closely-matched teams on the horizon, putting them under equal pressure to get more points on the board.
Ralph Hasenhuttl was not shy in criticising his players after last weekend's 3-1 defeat at West Ham United, a setback which has breathed new life into the Hammers' season.
The same kind of result will do the same for Newcastle, and it would pull the Saints into closer proximity to the pack of teams who are scraping below them.
Although Hasenhuttl's team should have enough quality to remain at English football's top tier, they require another three points as soon as possible to ease the tension at St Mary's.
Southampton Premier League form: LWLLWL
Southampton form (all competitions): DLLLWL
Newcastle United Premier League form: WDDLLD
Newcastle United form (all competitions): DWLLDW
Despite spending time at right-back in recent weeks, James Ward-Prowse is expected to return to central midfield for this contest.
After the win at West Brom, Bruce must decide whether to make sweeping changes to a team which impressed against the Championship leaders.
Southampton possible starting lineup:
McCarthy; Walker-Peters, Stephens, Bednarek, Bertrand; Armstrong, Ward-Prowse, Hojbjerg, Djenepo, Ings, Long
Newcastle United possible starting lineup:
Dubravka; Manquillo, Lascelles, Fernandez, Rose; Hayden, Bentaleb; Lazaro, Almiron, Saint-Maximin; Joelinton
We say: Southampton 2-1 Newcastle United
Although Newcastle will have more belief after their display in midweek, Southampton are well rested for an important game in their season. We feel that, and Newcastle's second trip South in the space of a few days, could prove crucial at St Mary's.