Payet will be out until February while Valencia's injury is also expected to be long-term.
It is the worst possible timing for West Ham boss Slaven Bilic who takes the Irons to fierce rivals Spurs after the international break with the sides neck and neck in the Premier League table just outside the Champions League places.
The Hammers hope to have star striker Diafra Sakho, who is arguably as important to Bilic's freeflowing attacking style as Payet, back for the big derby.
Alex Song also has an outside chance of making the squad after playing his first football this season in a friendly against Crystal Palace on Wednesday afternoon.
Taking the injuries into account and the quality of the opposition given that their upwardly mobile London rivals are in red hot form, a draw would represent a good result for the Hammers.
There are three crucial changes the former Croatia boss should make to have a chance of adding Tottenham to the list of scalps West Ham have already taken on the road this season including Arsenal, Liverpool, Manchester City and Crystal Palace.
1) Bring Antonio in from the cold
Since signing from Nottingham Forest for £7 million in the summer Michail Antonio has barely featured under Slaven Bilic. The powerful, pacy winger with an eye for goal and the spectacular is very similar in style to Victor Moses who will be occupying the other flank giving the Hammers plenty of pace to rediscover the counter attacking style that has served them so well this season. He would also be something of an unknown quantity to Tottenham's management and players which could count in West Ham's favour. What better way for Antonio to announce himself to the club's fans than put in a great performance on his full debut against one of their biggest rivals? He and Moses could also switch flanks very easily if needed.
2) Play Lanzini in the Payet role
Little Manuel Lanzini has been slowly but surely emerging from Dimitri Payet's shadow this season with some sparkling displays in midfield. The 'little Jewel', as he was dubbed in his native Argentina, has been in fine form of late scoring against Crystal Palace and Everton and turning in man of the match performances. With Payet ruled out Bilic should move Lanzini further forward in the role usually occupied by the Frenchman. There he will only have to beat one or two Spurs players to be through on goal or set up a chance for one of his teammates. Noble and Kouyate will have to sit a little more than usual to compensate as the home side will be a major threat themselves. Moses and Antonio will also have to be willing to do as much work going back as they do going forward.
3) Bring Sakho in to replace Carroll
Sakho's importance to Bilic's freeflowing attacking style has never been more evident than in the two games he has missed through injury in recent weeks. It is not just the Senegal star's goals but his all action performances, chasing and harrying the defenders, running the channels and giving the opposition a torrid time. Sakho opens up space for his teammates to exploit and with the infinitely less mobile Andy Carroll up front in his absence the Hammers have been nowhere near as dangerous going forwards. If Sakho is back, though, it is bad news for Mauricio Pochettino's side who will face a different animal altogether. He scored in the game at White Hart Lane last season and was the man of the match as Spurs snatched a last gasp 2-2 draw. The derby is sure to be a tight affair and Sakho could well be the difference between the two sides.
With that line-up West Ham still have plenty of talent to call on if things don't quite work in their favour. Song could come on to get his first taste of competitive action and add immense quality to the midfield while Mauro Zarate and Carroll would also make good options from the bench, as has been proved against Palace and Chelsea already this season, after Sakho has tired out the Spurs defence.
So is this how Bilic will line-up at White Hart Lane next Sunday?