It will be the first time the two clubs have met for a competitive fixture, but the visitors will not be unfamiliar to United boss Erik ten Hag, who had three stints with the Eredivisie outfit as a player, from 1989 to 2002, making 257 appearances for the club in total.
There will be no sentimentality from the Dutchman on matchday, however, as he looks to lead his Reds to three points in the new-look Europa League format.
Here's everything you need to know about the upcoming clash...
HOW TO WATCH: UNITED V TWENTE
The game is scheduled to kick off at 20:00 BST on Wednesday 25 September at Old Trafford, and will be shown live on TNT Sports 1 and discovery+.