His win sets up the first all-American final in seven years. The 21-year-old Querrey ended Santoro's dominance on Newport's grass courts. Santoro, the second seed, was 12-0 and had lost just one set before the upset.
Before play, Monica Seles highlighted the 2009 class that was inducted into the International Tennis Hall of Fame.
The third-seeded Querrey, looking for his second ATP event title, will face lucky loser Rajeev Ram, a 6-3, 6-4 winner of Belgium's Oliver Rochus, on Sunday. He had 18 aces against the 36-year old Santoro, four coming in the tiebreaker.
"Obviously I served incredibly," Querrey said. "I was placing it well. A lot of aces. If he dictates, he's tricky."
Querrey won his first career event in Auckland in January. The 25-year old Ram will be playing his first ATP final.
"I had a pretty good feeling that this could be a great week for me," Ram said. "I felt good coming in. Granted, I didn't know I'd make the finals."
Santoro, the oldest active singles player on the ATP Tour who said earlier in the week that this is his last season on the tour, didn't have an answer for Querrey's big serve with his unique style of two-handed cuts and slices.
"He was serving very good," Santoro said. "I will remember this tournament forever for the record I have."
Taylor Dent beat James Blake in the 2002 final.
Ram withdrew from his qualifier match Monday, but was the lucky loser with top-seeded Mardy Fish withdrew to replace Andy Roddick on the United States Davis Cup team.
Roddick withdrew with an injury after his epic Wimbledon final loss to Roger Federer.
The 35-year-old Seles was enshrined during a ceremony on Newport's grass courts. She was the world's No. 1 women's player for 178 weeks and won nine Grand Slam singles titles.
Donald Dell, Andres Gimeno and Dr. Robert Johnson were also inducted into the Hall of Fame.
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