Contrastingly, Spurs sit pretty at the top of the table and will be looking to maintain their 100% start to the season under new boss Nuno Espirito Santo.
Out of the two sides, Spurs certainly have the biggest selection headache after the international break.
Cristian Romero, Davinson Sanchez, and Giovani Lo Celso are all required to quarantine after travelling to South America for their World Cup qualifiers, despite Premier League rules.
Both Ryan Sessegnon and Oliver Skipp have picked up knocks whilst on England duty with the U21s, with Skipp to be assessed closer to the game.
What could be the most significant absentee is Son Heung-Min, who has sustained a calf strain whilst away with South Korea. He remains a doubt.
Steven Bergwijn has also picked up a slight injury with the Netherlands so Bryan Gil could make his first Premier League start.
There could also be a debut for Emerson Royal, who joined on deadline day from Barcelona and looks to be needed immediately.
Finally, Tanguy Ndombele remains on the sidelines after failing to secure a move away before the transfer deadline.
Will Hughes and Odsonne Edouard were added to Palace's new-look squad in the last week of the window, with both fully fit to make their debuts.
Another new signing Michael Olise is close is expected to make the bench as he fights to get fit after a back injury.
Club captain Luka Milivojevic is also hoping to return after personal issues have ruled him out so far this season.
Eberechi Eze and Nathan Ferguson remain the only long-term injury issues for Crystal Palace.
Crystal Palace: Guaita, Ward, Geuhi, Andersen, Mitchell, McArthur, Kouyate, Gallagher, Ayew, Zaha, Benteke.
Tottenham Hotspur: Lloris, Emerson, Tanganga, Dier, Reguilon, Winks, Hojbjerg, Alli, Moura, Gil, Kane.
Ones to watch
Tottenham are likely to boast several changes with so many players unavailable for various reasons.
New right-back Emerson will be one to keep an eye on as he is likely to be thrown straight into the starting lineup after his move.
Emerson impressed massively on loan at Real Betis last year and adds depth to a position where Spurs were lacking quality.
Bryan Gil is also likely to get his first Premier League start after only starting in European games so far.
The 20-year-old is a hugely exciting talent with bags of potential, a player who could become important for Spurs if he can adapt to the physicality of the Premier League.
For Palace, as always, Wilfried Zaha remains the key player to watch and the biggest threat going forward.
The Ivorian has yet to score this season and will be eager to open his account after having his best goalscoring season last year.
New signings Michael Olise, Will Hughes, and Odsonne Edouard could all potentially make their debuts this weekend, and Palace fans will be keen to see how they get on.
Spurs have been a thorn in Palace's side for the last few years, with the Eagles' only recent victory coming in the FA Cup in 2019.
Palace's three visits to the new Tottenham Hotspur Stadium ended in 4-0, 4-1, and 2-0 defeats, respectively.
However, Selhurst Park seems to be a different story where Spurs have drawn 1-1 in the last two seasons.
There are certainly positives to take from the home form and Palace will be hoping to go one step further this season and secure a victory.
Head-to-head last six games:
07-03-2021: Tottenham 4-1 Crystal Palace
13-12-2020: Crystal Palace 1-1 Tottenham
26-07-2020: Crystal Palace 1-1 Tottenham
14-09-2019: Tottenham 4-0 Crystal Palace
03-04-2019: Tottenham 2-0 Crystal Palace
27-01-2019: Crystal Palace 2-0 Tottenham (FA Cup)
Where to watch
The kick-off is scheduled for 12.30 pm on Saturday, September 10, 2021.
The game is live on BT Sport 1 from 11:30 AM, and you can also follow all the latest updates here on VAVEL.