Simon was called up to replace injured Gael Monfils this week. He has never beaten Isner and could not cope with the American's big serve. Simon also struggled with his own serve on the outdoor clay at Monte Carlo Country Club.
"I took to the court very confident," Isner said. "I played very well. Simple as that."
"We'd love to be up 2-0, but 1-1 seems just about right and tomorrow will be a great doubles," U.S. captain Jim Courier said. "John did what he is supposed to do, which is to be emphatic and dominant."
The Bryans, the world's top-ranked doubles team, are unbeaten in Davis Cup since losing to France in 2008, when Llodra played with Arnaud Clement.
"We'll be in a great position if we win," France coach Guy Forget said. "If we lose, it will be difficult."
Like France, the U.S. is not at full strength. Harrison was playing his first meaningful Davis Cup match. He replaced ninth-ranked Mardy Fish, who pulled out this week because of fatigue.
In the other quarterfinals, host Czech Republic and Serbia were 1-1; Spain was up 2-0 on visiting Austria; and host Argentina was tied 1-1 with Croatia. The semifinals are in September.
Isner had nine aces broke Simon's serve four times. Simon, who dropped to 0-3 against Isner, failed to convert any of his five break-point chances.
"I could have made more first serves," Isner said. "But my forehand was on and I was going for it. I wasn't holding back and that was the game plan."
The 11th-ranked Isner took control when a double-break point put him ahead 4-0 in the second set. The third set was more competitive, but Simon failed to take his chances.
Still, Simon kept chipping away. When Isner missed an easy volley at the net, Simon got his chance to pull back a set with Isner on his second serve. But the American kept his cool, and his forehand winner down the line got him out of danger.
Earlier, the sixth-ranked Tsonga found it tough at times against Harrison. The American's aggressive play forced Tsonga to hurry shots as he tried to shorten rallies.
"I hope I play better in my next game (against Isner on Sunday)," Tsonga said. "I had to battle and it worked out quite well for me. Despite losing that third set, I still tried to play my own game."
Tsonga broke serve in the 12th game to take a laborious opening set in 54 minutes. He then began to find his range as Harrison's temper frayed.
"His major weakness is that he is very, very nervy," Tsonga said. "I knew that if I held on longer than him, it would be to my advantage."
Harrison smashed his racket into the ground following his double-fault that gave Tsonga a 3-1 lead in the second set.
"I never double-fault that much, which is funny," Harrison said. "The sun was against me on that side, and so was the wind."
Harrison, ranked 66th, was far from intimidated and applied the early pressure. But when Tsonga broke in the fourth game of the second set for 3-1, Harrison took it out on his racket, whacking it so violently the frame bent into a right angle.
"You look at him and think 'OK, he's not feeling great,'" Tsonga said.
That prompted Courier, a former two-time French Open champion, to have a word with Harrison. Courier offered a sympathetic ear at the end of the second set, nodding while Harrison spoke as they plotted strategy.
"I agreed with him that my balls were landing a bit short, and that (Tsonga) was playing the match on his own terms," Harrison said.
Their chat seemed to work. Harrison beat Tsonga in the third set, breaking his serve three times.
"I think he's an unpolished diamond," Courier said. "You don't want to snuff out someone's fire. Ryan is a high-energy guy. My job is to help him nurture that energy."