Greg Woods, head coach of Keys, says Friday night's game at Rodney Parade is one his team cannot afford to lose.
"We've got to win and we've said this for a couple of weeks now," he said.
"If we lose, we're out of the race a little bit. More importantly, it's a Gwent derby and there's no more motivation needed than that."
Woods' side were 29-9 winners of the reverse league fixture at Pandy Park back in December but the Black and Ambers got revenge in the British & Irish Cup.
Llanelli and Llandovery are both chasing Keys hard but Woods says his side are ready to go.
"It's our biggest fixture of the year and the fourth time we've played them this season," he argued.
"It's our very own Judgement Day before the main event at the stadium on Saturday!
"We're not looking at the league ahead of this game. It's a one off derby we need to win. We've had a couple of weeks off and we're raring to go."
Newport meanwhile sit in mid-table with no chance of reaching the play-offs. And although they have little to play for, their head coach Sven Cronk has challenged his team to build some momentum with next year's campaign in mind.
"There's always added spice in these sorts of games and the same can be said for Friday night - it will be hotly anticipated," he said.
"We're looking forward to it but we're under no illusions that we've underperformed this year. We know we've got to improve and I think we can do that."
The Black & Ambers have shown signs of their potential, a narrow home win over league leaders Pontypridd a good example.
But their inconsistency has been a source of frustration to Cronk.
"We've had injuries to key personnel at key times - that hasn't helped us but that's no excuse. Other teams have suffered the same thing," he added.
"We've lost too many games, drawn two and we've got to learn from that. We have to close these sorts of games out.
"Keys are flying high and always give it everything but we want to solidify our performances, build some consistency and look forward to next season."