The duo now have eight days to get fit before they face Liverpool at their brand new stadium on January 11.
If both are out, it will leave Jose Mourinho seriously short of options up front and in central midfield for a game Spurs desperately need a result from as they hunt for a place in the top four.
Kane left St Mary’s on New Year’s Day on crutches after he appeared to tweak his hamstring after putting the ball in the back of the net – although his strike was ruled out for offside.
Meanwhile, Ndombele looked to have injured his groin just 25 minutes into the match, which was a huge blow considering his impressive performance to that point.
Now, having just drawn with Norwich and lost to Southampton, Spurs must battle league leaders Liverpool, who are romping to the Premier League title, without two of their best players.
Kane’s injury is a particular blow but perhaps unsurprising given he had played 90 minutes in every single game under Jose Mourinho apart from the loss away to Bayern Munich in the Champions League.
Ndombele, meanwhile, appeared to have concerns about his conditioning prior to the festive period but was started in two consecutive games by the Portuguese manager.
It now leaves Spurs seriously short with 17-year-old Troy Parrott the only recognised specialist striker in the squad, although Heung-Min Son, Lucas Moura, and Dele Alli have previously been used as forwards.
In midfield it is a more complex matter; Ndombele has been far and away the best player in the middle of the park this campaign but his fitness issues have limited his impact.
Fans had tired of the Harry Winks and Moussa Sissoko combination which lacked attacking output and any really creativity and thrust.
Eric Dier is still regaining his fitness after his illness having suffering a virus over the festive period, and Oliver Skipp is still considered to be learning the ropes.
Giovani Lo Celso, who spent his time at Paris Saint-Germain as a central midfielder has, slightly oddly, mainly been used in an advanced role, while Victor Wanyama has only made two substitute appearances this term and is set for a winter transfer.
Elsewhere, Christian Eriksen has played in deeper positions this season but has also spent a lot of time on the bench due to his seemingly impending exit.
All of this will leave Mourinho tearing his hair out as the unstoppable juggernaut that is Liverpool rolls into town in nine days.
So how could Tottenham look for the clash? talkSPORT.com take a look.