The two sides round out Group B – which also features England and their opponents today, Iran – and they are expected by most fans to be vying for second place in the pool.
That notion follows the assumption that England will qualify first in the group, but major tournaments usually carry a number of surprises, and Wales will be looking to replicate their Euro 2016 feat of finishing ahead of the Three Lions.
USA, meanwhile, had encouraging World Cup campaigns in reaching the last 16 in 2010 and 2014, but they failed to qualify for the 2018 edition of the tournament in Russia. As such, they will be especially keen to stick around in Qatar.
Here’s all you need to know.
When is it?
USA vs Wales will kick off at 7pm GMT (10pm local time) on Monday 21 November.
The match will take place at the Ahmad bin Ali Stadium in Al Rayyan.
How can I watch it?
The game will air live on ITV 1, and it will stream live on ITVX – previously called ITV Hub.
What is the teams news?
USA midfielder Luca de la Torre is an injury doubt, having sustained a hamstring injury while on club duty with Celta Vigo in late October.
For Wales, Joe Allen has similarly been battling a hamstring issue, but coach Robert Page will be hopeful that the Swansea midfielder can regain fitness in time to help his team here.
USA – Turner, Robinson, Ream, Zimmerman, Dest, Adams, McKennie, Musah, Pulisic, Ferreira, Weah
WAL – Hennessey, Ampadu, Rodon, Davies, Roberts, Allen, Ramsey, Williams, Johnson, Bale, James
USA – 6/4
Wales – 21/10
Draw – 19/10
Most observers expect these two teams to be vying for second place in Group B, with England favourites to qualify atop the group. As such, this game could end up deciding which of these nations advances to the knockout rounds, meaning it may well be an especially tense affair. That could just lead to a low-scoring draw. USA 1-1 Wales.