With the fixture at Estadio El Teniente falling outside a designated international window, both teams are largely without their contingents of foreign-based players.
For the US, that means going without the likes of Aston Villa goalkeeper Brad Guzan, Stoke City defender Geoff Cameron and Nantes midfielder Alejandro Bedoya.
A total of eight uncapped players have been included in Klinsmann's 23-man squad, but the addition this week of Tottenham full-back DeAndre Yedlin - one of only two Europe-based players set to take part on Wednesday - will have come as a welcome boost.
The experience of old heads such as Clint Dempsey, Michael Bradley and Jozy Altidore should help the new recruits settle, and Klinsmann hopes they can hit the ground running, despite the American domestic season having finished at the beginning of December.
"These guys have put in a lot of work these past two weeks of training for what is essentially their pre-season, and now it's time to focus on getting a result against a difficult opponent in Chile," he said.
"We know it's going to be a challenging situation, but these are the types of opportunities we need to keep growing."
Another one of Klinsmann's more experienced players, Jermaine Jones, is determined to do all he can to help.
"After the World Cup and after the good year we had, in the first game, it's important that we come out with a win," he is quoted as saying by Fox Sports. "We have a lot of players with experience.
"We need to step on the field, try to take the young players with us and play a good game."
History will be made as Brek Shea and Mix Diskerud become the first Orlando City and New York City players respectively to represent the US since the two sides became part of MLS.
Chile, meanwhile, step up their preparations for hosting the Copa America later in the year, and will be looking for a return to winning ways after closing 2014 with a 2-1 defeat to Uruguay.
Like the US, Chile are without a host of experienced internationals, with Claudio Bravo, Gary Medel and Alexis Sanchez among the players remaining with their clubs.
Indeed, coach Jorge Sampaoli - named sixth-best national team coach of 2014 as part of a recent study by the International Federation of Football History and Statistics - has picked a squad entirely comprised of Chile-based players.
