Cresswell has played in all 56 of West Ham's Premier League games since signing from Ipswich Town for a bargain £3.5 million back in the summer of 2014.
But the ever present left back, who scored a brilliant goal in the 1-1 draw at Aston Villa on Boxing Day, will miss today's match against the Saints breaking his brilliant run.
That's according to Jack Sullivan, the son of Hammers co-owner David, who has confirmed on Twitter the Liverpudlian will almost certainly sit it out against Ronald Koeman's men.
Responding to a fan asking if Cresswell was injured for the visit of the Saints, Sullivan said on Twitter: "Looks unlikely, but it should be small!"
Looks unlikely for tomorrow, but it should be small! https://t.co/ULMuNa5gdY— Jack Sullivan (@jsullivanwhu) December 27, 2015
While Hammers fans will be bitterly disappointed to lose yet another important player to injury, it is good news that Cresswell will not be out for too long.
The ex-Tranmere defender is one of West Ham's most cherished players and was handed a new five-year contract with the option of a further two years back in the summer.
And the Hammers showed just how highly they rated Cresswell by moving quickly to ward off any interest with a bumper new deal running until 2020, with the option for a further two years after that.
So where does that leave Slaven Bilic when it comes to replacements?
Young Scottish left back Stephen Hendrie has not made his first team bow since officially joining West Ham back in July - he signed back in January - but was on the bench against Villa.
When Cresswell got injured, though, Bilic opted to bring on the experienced Alex Song instead for the last 15 minutes at Villa Park with winger Michail Antonio switching to left back instead.
Hendrie is highly rated by the Hammers and Scotland, though, and now would be the perfect time for him to prove he is ready to step up to the challenge of Premier League football.
With West Ham short of attacking options and Antonio performing well in recent games, it would be a shock to see him moved to left back from the start.
Another option for Bilic would be to play Carl Jenkinson at left back, if James Tomkins is available to play at right back.
Jenkinson is a right back by trade but has played out on the left wing as a substitute on a few occasions this season at Leicester City in the League Cup and against Manchester United at Old Trafford.
Academy youngster Lewis Page is the alternative and he has at least played a couple of competitive matches for Bilic's side.
He suffered an injury, though, and spent an extended spell on the sidelines.
Page, 19, impressed Hammers fans with his tough tackling and willingness to get forward so would be a popular choice and Bilic does has form for promoting young talent.