The two sides meet at Llandarcy Academy of Sport, with the game screened live via the S4C website. Kick-off is at 2.30pm.
Wednesday's fixture is the first of this season's competition for Neath Port Talbot while Gower College will be looking to bounce back from a disappointing 64-3 defeat to Cymoedd College in the opening round last week.
"Cymoedd are a very good side. They've got a number of boys from the Blues Academy and I think we were a little bit undercooked," said Gower College Director of Rugby Daniel Cluroe.
"We weren't ready for the pace or intensity of their game and we've learnt the lessons from that."
Looking ahead to Wednesday's game against regional rivals Neath Port Talbot, Cluroe added: "It's a huge local derby for us, not just in terms of local bragging rights for the boys but also for the two colleges as well.
"It's always a very close game between us but I think the weather is going to play a big part on Wednesday.
"There's extra spice in that the boys from both colleges play club and regional rugby together. Neath Port Talbot always have a dangerous back line regardless of how many of their regional players will be available."
Gower include Wales Under 18 cap Jonathon Fox at No. 8 with Matthew Aubrey and James Lewis at half back. Neath Port Talbot on the other hand boast internationals Adam Beard and Joe Thomas. Beard is partnered by Oliver Thompson in the second row.
Max Howells, Director of Rugby at Neath Port Talbot College, said: "We're slowly growing in terms of temperament and intensity and we are prepared as well as we can be for this first game.
"We've got everyone fit and we're looking forward to it. It's going to be an interesting game as obviously a lot of the players know each other from the Ospreys Under 18 side.
"Gower are a big outfit with a physical pack so we hope to get the better of them in that department.
"We must be realistic and respect the teams we play against but we want to top the group by the end of October. We'll take one team at a time but that's certainly our target."
In the other fixtures to take place this Wednesday, Bridgend College will be looking to make it two wins from two as they host Pembroke while last year's champions Coleg Sir Gar travel to Newport.
Sir Gar were 67-0 winners over Pembroke last week while Newport showed glimpses of the talent in their side albeit in defeat to Bridgend.
Elsewhere, Coleg Gwent host Cowbridge High School in a 2pm kick-off at Waunfawr Park with Llandovery College travelling north to Parc Eirias to take on Llandrillo College in Colwyn Bay.
You can watch highlights of the fixture between Neath Port Talbot College and Gower College on Rygbi Pawb on S4C at 10.30pm on Wednesday evening.
WRU Wednesday Under 18 League fixtures: (Round Two - Wednesday, October 2.)
• Bridgend College vs. Pembroke
• Newport High School vs. Coleg Sir Gar
• Coleg Gwent vs. Cowbridge High School (KO 2.00pm)
• Llandrillo College vs. Llandovery College
• Neath Port Talbot College vs. Gower College (live via www.s4c.co.uk KO 2.30pm)