The second-seeded Roddick struggled to maintain any consistency, landing only 55 percent of his first serves and was out-aced by the Frenchman 7-3 during the 69-minute match.
"It was just a bad night. I really don't have much of a defence for it," a frustrated Roddick softly told reporters.
"I really don't feel you can defend it.
"I didn't feel right physically, I didn't feel right mentally. It was just a pretty bad effort," he added.
In other matches, top seed Tomas Berdych of the Czech Republic, playing in his first tournament since losing to Rafael Nadal in the Wimbledon final, overcame a second-set wobble to edge Andrey Golubev of Kazakhstan 6-3, 5-7, 7-5.
Also advancing to the quarter-finals of the $1.2 million hardcourt tournament were third seed Fernando Verdasco of Spain and fourth seeded Marin Cilic of Croatia.
The 27-year-old Roddick, a three-times Washington champion, said he has felt sluggish over the last few weeks, admitting "something is just not right".
"I'm a little concerned about that," Roddick said.
"Feeling lethargic and not all there energy-wise, that's not fun for me. I don't enjoy nights like tonight.
"It could be something simple, maybe a vitamin deficiency. I promise you I'm going to figure this out before I do that again. That's not what I built my reputation around," he added.
MADE MISTAKES
Simon, ranked 33rd and seeded 13th, made the most of his chances, converting three of five break-point opportunities against Roddick while never losing his own serve.
The Frenchman broke Roddick in the second game of the final set to take a 2-0 lead and served out the contest.
"I managed to return his serve today," said Simon, who had failed to win a set against Roddick in their prior two meetings.
"When he decided to wait (and play from the baseline), I was more consistent than him.
"And when he decided to attack and be more aggressive, he made some mistakes," he added.
Roddick, playing in just the second tournament since Wimbledon, refused to blame his performance on his light schedule.
"There is a reason that I haven't been playing a lot," he said.
"It's because I've been playing like crap. I felt I didn't do one thing right tonight.
"I honestly don't think it would have mattered who I played," he added.
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