The Glasgow Warriors pair Gordon Reid (prop) and Finn Russell (stand-off), and the London Irish back-row, Blair Cowan, will start their first international outing at the BBVA Compass Stadium, while prop Alex Allan (Glasgow Warriors) and scrum-half Grayson Hart (Edinburgh) could debut from the bench.
Reid, an unused replacement in the 2012 Autumn Test match against Tonga, will keep experienced company in the forwards, starting alongside Scott Lawson (hooker) and Geoff Cross (prop), and familiar locking duo Richie Gray and Jim Hamilton.
Cowan is joined in the back-row by Alasdair Strokosch (Perpignan) and No.8 Johnnie Beattie (Castres), the latter starting his first match since injuring his ankle in the RBS 6 Nations match against France in March.
In the backs, 21 year-old Russell will be accompanied by scrum-half and captain, Greig Laidlaw, who will share the responsibility of orchestrating a physical midfield partnership of Duncan Taylor and Sean Lamont, and a dynamic back-three trio of Tim Visser, Sean Maitland and Stuart Hogg.
Scotland head coach Vern Cotter, said: "There's a lot of excitement within the team leading into this Test.
"There are players who are going to earn their first cap for Scotland, and there are those who see this as a chance to stake a claim for the Rugby World Cup squad in 2015, as there are only a certain number of opportunities remaining for players to express and prove themselves."
He continued: "We need to look at our options in decision making and game-controlling and Finn [Russell] has been playing very well of late for Glasgow Warriors, and this is a good chance for him.
"I like what he offers. He seems a composed young lad for a 21 year-old, who controls games and will obviously grow in this position as he develops.
"Gordon [Reid] has also impressed with Glasgow. He offers size and mobility and it'll be interesting to see what he brings to the forward engagement, outside of the set piece.
"I want to see somebody who's aggressive, who cleans out, who carries and shifts bodies, so this is Gordon's opportunity to show us what he can do in those areas of the game.
"Finally, injuries to Ross Rennie and John Barclay give Blair [Cowan] a chance to compete for the back-row jersey. He's an out and out No.7: he's quick on his feet, can carry, and is quick over the ball.
"We're looking for a genuine seven who gives us options, so I'm looking forward to seeing what he can do on the paddock after playing well for Scotland A earlier this year."
The match against the USA is the first of a four Test Summer Tour and will be a fourth meeting between the sides, with Scotland winning the three previous encounters.
The most recent was during the 2003 Rugby World Cup, when Scotland ran in five tries in their 39-15 win, after home and away test wins in 2002 (in San Francisco) and 2000 (at Murrayfield).
Today some eight places in the world ranking separate Scotland from their 18th placed hosts, though Cotter was quick to dispel the relevance of such a gap.
"I think it's important that we have a very physical approach to the game", he added. "We're in for a tough Test because they [USA] come out quickly in defence to try and stress you, so we'll have to keep composure under that kind of pressure.
"If they come out of the line I want the players looking up and seeing what's in front of us. We're on a dry track and we want to put speed into our game. We want to be able to play, and play across the park, as well as be intelligent with the way we use the ball. It's a matter of communicating, staying calm and focused on our game, and the game we want to develop."