The game, which is a World Cup European Pool A qualifying match, takes place on Saturday October 15, at Parc Stebonheath.
It kicks off at 3pm, and commentary will be available in both Welsh and English throughout the UK, with the English version available on the red button service.
It will be the first time that S4C has shown live rugby league since 2008, and will also be the first time that the Welsh national RL side has featured on the channel since 1995.
“This is tremendous news,” said Wales coach John Kear.
“S4C showed highlights of our European Championship winning campaign and the fact that they’ve now chosen to show our World Cup game against Serbia live and free to air is testimony to the improved performances of the squad and awareness of the game.
“S4C’s broadcast will bring a new audience to the game and we want the television public to enjoy it. We now need to ensure that the ground is full to add to the atmosphere and then nail that result.”
S4C sports editor Sue Butler is delighted that the channel is showing the match.
“We’re very pleased to include live coverage of this Qualifiers match as part of our sports portfolio,” she said.
“We wish the side the very best of luck as they represent Wales on an international stage and look forward to providing this exclusively live broadcast.”