Simon broke Roddick's serve in the first game of the match and had little trouble with the 12th-seeded American.
While the sky was clear at the Foro Italico, gusty winds created difficult conditions.
"He moves really well, which you don't want to see when you're short of matches, and on a day like today, where you're not getting clean hits much at all," Roddick said. "As soon as we got into rallies it became a battle of not really ball striking but movement. I was coming in second most times."
Another American, 11th-seeded Mardy Fish, rallied to beat Santiago Giraldo of Colombia 4-6, 6-2, 6-2. No. 15 Viktor Troicki of Serbia edged Nikolay Davydenko of Russia 6-4, 7-5, and Italian Potito Starace eliminated Australian Open quarterfinalist Alexandr Dolgopolov 6-3, 6-3.
"I have no energy. I'm going to take some tests and hopefully it will pass," Monfils said.
In women's action, Ekaterina Makarova of Russia beat last year's surprise champion, Maria Jose Martinez Sanchez of Spain, 6-0, 5-7, 6-4, and Greta Arn of Hungary eliminated 11th-seeded and two-time finalist Svetlana Kuznetsova 3-6, 7-6 (4), 7-6 (9).
Also, ninth-seeded Marion Bartoli of France beat Spanish qualifier Arantxa Parra Santonja 6-2, 6-3; and another Spanish qualifier, Anabel Medina Garrigues, eliminated 2005 runner-up Patty Schnyder of Switzerland 6-3, 6-2.
The men's and women's tournaments are being played simultaneously for the first time in 33 years.
Roddick hit only nine winners to Simon's 23 and committed 27 unforced errors to his opponent's 18. The big-serving American also trailed 4-1 in aces.
Roddick also lost his opening match at last week's Madrid Open, falling in three sets to 160th-ranked Italian qualifier Flavio Cipolla.
"The last couple weeks I haven't felt comfortable out here," Roddick said. "I feel great physically. I feel fine, there's no excuses."
With the French Open less than two weeks away, Roddick's last chance to hone his game will come in Nice, France, next week.
"Hopefully I can do something there," he said.