The season's first midweek round of Premier League matches brings an opportunity for the Saints, now 2/1 from 13/8 to make the drop, to climb out of the bottom three.
Ralph Hasenhuttl's side finally got their first home win of the season against fellow strugglers Watford, who sacked head coach Quique Sanchez Flores in the wake of defeat at St Mary's.
Southampton won't face a team that are currently in the top 12 in their next four Premier League fixtures and should take this opportunity to move away from trouble - and drag some of their rivals into more difficulty.
Norwich could not back up their surprise 2-0 away win at Everton with another at home to Arsenal on Sunday, with boss Daniel Farke left bemoaning a controversial video assistant referee intervention at Carrow Road.
The Canaries' relegation odds haven't changed much as a result of their 2-2 draw and they are still the 4/11 favourites to return to the Championship next term.
Norwich host in-form Sheffield United and travel to high-flying Leicester City in their two other pre-Christmas fixtures after the Southampton game, so the importance of picking something up from Wednesday's clash is clear.
Everton could drop into the relegation zone this week if they suffer a third straight defeat in the Merseyside derby. The Toffees are a best-priced 12/1 to lose their top-flight status for the first time in over 60 years.
Newcastle are 14/5 to be playing Championship football next term despite pulling off one of the surprises of the weekend when they grabbed a 2-2 draw against champions Manchester City.
The Magpies remain a point above Aston Villa, who have star man Jack Grealish to thank for a goal and an assist in their 2-2 draw with Manchester United.
Villa, who are 100/30 to go down, need Grealish to stay fit and in form if they are to avoid the ignominy of slipping out of the division again.