The Saints beat Swansea City 3-2 after extra-time in the third round, while the Sky Blues secured a narrow 1-0 win at home against Derby County.
Southampton bounced back from their 3-1 loss away at Wolverhampton Wanderers with a hard-fought 1-1 draw at home against Premier League leaders Manchester City in their most recent game.
The Saints, who sit 12th in the table and 10 points above the relegation zone, have now extended their unbeaten record at St Mary's to eight matches, albeit winning only three times during this run.
With no fears of the drop on their minds at present, Ralph Hasenhuttl's side may now target an FA Cup run, with a favourable fixture against lower league opposition to come this weekend in the form of Coventry City.
After claiming just three victories in 19 matches with the Sky Blues in all competitions between 1996 and 2008, Southampton have since won each of their last three meetings against them, most recently winning 4-0 on home soil in 2012.
Victory for the Saints this weekend would see them reach the fifth round of the FA Cup in consecutive seasons for the first time since 2004-05 and 2005-06.
Coventry's five-game unbeaten run away from home came to an end last weekend when they suffered a slender 1-0 defeat against Middlesbrough.
After a goalless first half, Andraz Sporar broke the deadlock just before the hour mark, which was enough to condemn the visitors to their ninth league defeat of the campaign.
Mark Robins's men have dropped down to 10th in the Championship standings, but they only sit five points behind sixth-placed West Bromwich Albion, with at least one game in hand on every team above them.
Coventry now switch their focus to the FA Cup, a competition they won for the first and only time in 1986-87. Since then, however, they have only managed to make it as far as the quarter-finals on two occasions, in 1997-98 and 2008-09.
Only once in the last 12 years have Coventry progressed to the fifth round, and their hopes of reaching the next stage seem slim against Premier League opposition. The Sky Blues have lost three of the previous four FA Cup meetings with Southampton, and have been eliminated from six of their last seven FA Cup ties against top-flight opponents.
Moussa Djenepo is also available after returning from international duty with Mali at the Africa Cup of Nations, and he will be competing with Mohamed Elyounoussi, Stuart Armstrong and Nathan Redmond for a starting spot on the flanks.
Striker Adam Armstrong, who scored 20 goals in 40 appearances on loan at Coventry in 2015-16, could start his first game in nearly a month alongside either Armando Broja, Che Adams or Shane Long, while former Sky Blue defender Jack Stephens may also be handed a start at centre-back.
Southampton possible starting lineup:
Forster; Livramento, Stephens, Lyanco, Perraud; S. Armstrong, Ward-Prowse, Romeu, Elyounoussi; A. Armstrong, Adams
Coventry City possible starting lineup:
Wilson; Hyam, McFadzean, Clarke-Salter; Kane, Sheaf, Hamer, Maatsen; Allen, O'Hare; Gyokeres
We say: Southampton 2-0 Coventry City
Coventry have lacked consistency in recent weeks, winning three, losing three and drawing one in their last seven matches, and it remains to be seen which side will turn up at St Mary's.
The visitors will need to be on top of their game if they are to cause an upset this weekend; however, Southampton should have enough quality in their side to secure a routine win on home soil.
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