After his dream return to the NFL last week, Manning was given a rude awakening as the Falcons intercepted the Denver quarterback three times in the first quarter on the way to victory.
Manning missed last season due to neck surgery, leading Indianapolis to cut the four-times league MVP, but on his debut with the Broncos last week the 36-year-old showed he still had plenty to offer, leading the team to a 31-19 win over Pittsburgh.
Against Atlanta, however, Manning struggled to find his receivers and watched the home defence pick off his passes and race to a 20-0 lead.
He finished 24 of 37 for 241 yards, including a touchdown pass to Demaryius Thomas just before halftime.
The only other time Manning was picked off three times in the opening quarter was with the Colts in a 2007 game at San Diego.
Ryan was much more efficient than the four-time MVP, completing 24 of 36 for 219 yards. He extended their lead to 27-7 with a scoring pass to Roddy White in the third quarter before Manning led two drives that were both capped by short touchdown runs from Willis McGahee that pulled Denver (1-1) within six.
However, the Falcons were able to keep possession and run out the clock to seal the win.
Ryan finished with two touchdowns throws and no interceptions, while Manning threw for 241 yards and a touchdown to go with his three costly interceptions.
"We put ourselves in a hole," Manning said afterwards. "I thought we could find a little momentum there, find some rhythm, which we did.
"I thought we could give ourselves a chance to win. I never once thought the game was over. It would be difficult."
The near three-and-a-half hour match was marred by questionable decisions from replacement officials and long clock stoppage, but John Fox, the Denver coach, refused to cite that as an reason for the defeat.
"In this league, you have to overcome a lot of things," he said."We don't use officiating as an excuse."
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