Smith and Vargas meet in a must-win fight that will determine the next chapters of both careers.
The winner will close in on a shot at the title, while the loser will face questions over their future in the sport.
'Beefy' has been the more active of the two, with a KO win over local Liverpool rival Anthony Fowler in October following a harsh points defeat in Russia last May to Magomed Kurbanov, while Vargas has been out of the ring since tasting defeat for the third time in his career against Mikey Garcia in Texas in February 2020.
Saturday's fight has been on the cards for some time now, long before it was postponed in February after Vargas caught COVID, and there's been plenty of back and forth between the former world rulers.
Vargas has been sparring in the political sphere too, launching a campaign to run for Nevada's 4th US Congressional District, and while he believes he'll be the man to challenge for world honours once again, Smith feels the Las Vegas man is already looking at his next career and will pay the price in the Big Apple.
"You question if he wants to be here," said Smith. "I have this thing in my mind; he's running for Congress, he hasn't boxed for two years, he's only got one fight left on his contract, so is this his last hurrah? Give me one more payday and I'll move into politics?
"He's very good technically, he's got that typical Mexican American style and he likes to fight, meaning, he's more of a boxer but he doesn't shy away from a fight.
"I know he's a nice guy but for some reason, there's a bit of needle there. I boxed Sam Eggington in March 2019, and Eddie mentioned Jessie's name in the ring, and I thought, 'yeah, you promote him, I'd like that'. We jumped on it, he fought Garcia which was cool - but that was two years ago, and he could have fought me in those two years.
"I met Jessie at MSG at the Anthony Joshua vs. Andy Ruiz fight when Callum was on the card, and we shook hands on the fight, so it just did my head in a bit not because I was chasing him and he's a big money fight or a World title fight, I was after him because neither of us were going to get a title shot and it's a very good fight.
"When I look at the landscape of the 154lb division, I believe I can be World champion again. If I didn't, I would retire because I'm happy, I've got two lovely daughters, I've ruled the world - so I could retire a happy man.
"People would bite your hand off for the career I've had, but I am realistic when I look at the champions and contenders and think 'I can beat him, him and him' so I am not done yet, I still have that fire in me.
"He's only lost to Manny Pacquiao, Timothy Bradley, Mikey Garcia and soon, to Liam Smith. We're in boxing to be in good fights and he's one that I want to get rid of.
"Ultimately, I'm going to be too big and too strong for him. I'm a fully-fledged 154lber, I've been there my whole career and he's gone from light-Welter to welter and now super-welter. If you can make 147lbs you are not a proper 154lber just yet and I think that's going to play a part.
"Jessie - make sure you are ready. If this is your last hurrah, let's give the fans a great fight and one they can talk about.
"I do think that you are going to get that, I'm not just saying that, I like to be in good fights, I don't come to hold, I don't come to make it a bore fest or awkward; I come to fight and I think he's got that in him too, so I think you are going to get a good fight but a Liam Smith win."
Smith and Vargas clash on an historic night of action in New York, topped by Katie Taylor and Amanda Serrano becoming the first female boxers to headline the famous arena with Taylor's undisputed Lightweight championship on the line.