The midweek visit of the managerless Saints comes at the perfect time for Spurs, who are still reeling from their 4-2 setback at local rivals Arsenal.
Amid a run of 10 games between the start of December and New Year's Day, Mauricio Pochettino must decide whether to rotate his side for this Premier League clash.
Here, Sports Mole looks at how the Lilywhites could line up against Southampton.
Pochettino will without Vertonghen as a result of his late sending-off against Arsenal on Sunday, while a number of others will sit this one out through injury.
One man who featured late on in that last Spurs outing is Danny Rose, who is now in line to make his first start in two months if Ben Davies is given a breather, though Trippier does not quite appear ready to make a return on the right-hand flank.
Harry Kane seems certain to start up top, aiming to build on a record that has seen him score six goals in five meetings with Southampton, while Dele Alli has had a hand in eight goals across that same sequence.