The debutant trio are fly-half Finn Russell and prop Gordon Reid, both of Glasgow Warriors, plus London Irish flanker Blair Cowan. In addition, Cotter has chosen another two Test newcomers among the Scotland replacements, handing seats on the bench to prop Alex Allan, who has recently moved from Edinburgh to Glasgow, and Edinburgh scrum-half Grayson Hart.
Yet after praising the abilities of all five players, Cotter made it clear that the US team of today are a far better side than the one against which Scotland achieved comfortable wins in 2000, 2002 and 2003.
"Don't underestimate them, they are a very good side," he warned. "They are nowhere near the team they were, the way they were perceived fifteen years ago.
"They are developing their rugby, and they've got core players who are professional and who practise the same arts as our players. They pushed Ireland close here last year. They pushed the Maori All Blacks very close last year. They enjoy playing in Houston. There are a lot of challenges in front of us."
The biggest of those obstacles is unquestionably the heat and humidity that will still be at uncomfortably high levels even as the game kicks off at 7.30pm local time.
Cotter suggested that the versatile Cowan's selection for the first time - he was an unused member of last autumn's international squad - owed something to the environment they are going into.
"What [Cowan] does give us on a dry track is speed across the pitch," said Cotter. "He's quick. He'll apply pressure, which is what the game is about. And I'm sure he's looking forward to the game on Saturday."