Van Wyk, who was the Junior Springbok Player of the Year for 2021, and More will man the midfield for the Emirates Lions, with Manuel Rass providing cover from the bench.
Instrumental lock Reinhard Nothnagel wears the captain's armband in a fixture where the Johannesburg-based outfit will look to finish on a high in Newport.
Earlier this week, the Emirates Lions mentor stressed the need to look ahead, and his team's final Vodacom URC fixture is the ideal opportunity to explore new combinations.
"As mentioned last week, it gives us an opportunity as a franchise to cast our eye towards the future, and we believe that this group will form part of that core," said Van Rooyen.
"They'll be a few guys in the match 23 who will be relishing the opportunity to make a name for themselves against international opposition.
"In saying that, Dragons will be a tough outfit to play at a vibrant Rodney Parade. We've planned and trained well this week so the guys we’ll be up for it come Saturday."
Elsewhere, loose forward Jarod Cairns and tighthead prop Asenathi Ntlabakanye could make an appearance from the bench in this match, which is scheduled to kick off at 16h00 (SA time).
Emirates Lions: 15 Quan Horn, 14 Stean Pienaar, 13 Henco van Wyk, 12 Matt More, 11 Edwill van der Merwe, 10 Jordan Hendrikse, 9 Morne van den Berg, 8 Francke Horn, 7 Vincent Tshituka, 6 Sibusiso Sangweni, 5 Reinhard Nothnagel (captain), 4 Ruan Venter, 3 Ruan Dreyer, 2 Jaco Visagie, 1 JP Smith. Replacements: 16 PJ Botha, 17 Sti Sithole, 18 Asenathi Ntlabakanye, 19 Ruben Schoeman, 20 Jarod Cairns, 21 Andre Warner, 22 Manuel Rass, 23 Tiaan Swanepoel.