Southampton have enjoyed an impressive revival in recent weeks under Ralph Hassenhuttl, but are still not totally guaranteed of safety at this stage.
Consecutive losses mean they are just seven points clear of 18th-placed West Ham United, while they have won just once in their last four league fixtures.
They have also picked up just 11 points at St Mary's all season, winning three times - a statistic they will be hoping to improve on this Saturday.
Southampton have also conceded more goals at home than any other side in the division, with 30 goals scored against them at St Mary's in 13 matches.
However, their away form has been outstanding, with one of their six wins on the road coming against Aston Villa just before Christmas.
Dean Smith will have been livid after watching his side concede three sloppy goals in their loss to Spurs at Villa Park on Sunday.
Tyrone Mings will return to the starting lineup ahead of Saturday's meeting which should help bring more security at the back, but the absence of Wesley and John McGinn has been hurting their attacking play.
Villa have picked up just eight points on the road all season, managing two wins and conceding 26 goals.
Southampton Premier League form: WWLWLL
Southampton form (all competitions): LWDLLL
Aston Villa Premier League form: WLDWLL
Aston Villa form (all competitions): LDWWLL
Boufal's absence is not expected to be so long-term, while loan signing Kyle Walker-Peters has also been ruled out.
Jan Bednarek could return to the starting 11 after being left on the bench last time out.
Tom Heaton and Wesley will not be seen again this season after both suffered long-term knee injuries last month.
Southampton possible starting lineup:
McCarthy; Valery, Stephens, Bednarek, Bertrand; Armstrong, Ward-Prowse, Hojbjerg, Djenepo; Ings, Long
Aston Villa possible starting lineup:
Reina; Konsa, Mings, Hause; Guilbert, Nakamba, Luiz, Targett; El Ghazi, Samatta, Grealish
We say: Southampton 2-2 Aston Villa
In a meeting between the two sides with the Premier League's worst defensive records, goals will be expected. Southampton have struggled at home all season and Villa are in desperate need of a results, so a draw looks most likely.