Calzaghe is making the 20th defence of the title he has held since 1997 against the former reality TV star.
A 35,000 Millennium Stadium crowd will watch, with a huge worldwide audience.
With the Cardiff stadium's roof closed, it will be the biggest ever indoor boxing event in Europe, and the largest worldwide since the return fight between Muhammad Ali and Leon Spinks at the New Orleans Superdome in September 1978.
"I've been through years of frustration not getting the big fights, now I've got that recognition," said Welshman Calzaghe, 35, who holds a record of 42-0 (31 KOs), and will be equalling the number of defences made by Larry Holmes and Bernard Hopkins.
"If you can't get motivated to fight in front of 35,000 people, there is something wrong with you.
"There is still a lot of fire inside me. My book is not written yet and there is so much I still believe I can achieve.
"I have given Peter respect by getting into the best shape I have ever been in."
Should Calzaghe win impressively, a summer unification fight with Denmark's undefeated WBC and WBA champion Mikkel Kessler seems to have the backing of US TV money, but Manfredo insists he should not be overlooked.
The Rhode Islander, 26, holds a record of 26-3 (12 KOs), with impressive third-round stoppages of Joe Spina and Scott Pemberton in his last two fights.
But he is most famous for being the runner-up in the first US series of boxing reality TV show 'The Contender', and will be a huge underdog against Calzaghe.
"I have not spent 12 weeks away from my family to come here and be an opponent," said the challenger.
"I am here to be champion and I am not afraid of Joe or his reputation.
"I'm excited about the fight on Saturday night and I am convinced it is going to be my night.
"I am going to be the champion - and that's the mind I am going to have until Joe defeats me - if he does."
Ring legend Sugar Ray Leonard, offering advice to the Manfredo corner after introducing him to the world through 'The Contender', insisted Calzaghe is a future member of the International Boxing Hall of Fame.
"Win, lose or draw on Saturday and Calzaghe will be in the Hall of Fame, he is a true warrior," Leonard told BBC Radio Wales' 'Back Page' programme.
"His fame will rocket in the States after this thanks to Peter's celebrity.
"But I'm an optimist and I think that Peter can win. It's a once-in-a-lifetime opportunity for him and I can see in his eyes the eye of the tiger."