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.
"Anytime you come on the road and throw three interceptions in the first quarter you really put your team in a hole," Manning said after finishing with 241 yards passing and one score to go with the three costly turnovers.
"Three bad decisions. We'll learn from this and get better."
After the dreadful start, Manning composed himself and threw a touchdown to Demaryius Thomas just before the intermission to cut the deficit to 20-7 at the half.
Atlanta quarterback Matt Ryan 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 threw one touchdown pass in each half and had no interceptions.
"That was a good win for our team," Ryan said. "We're 2-0, it's a good start to our season but that's it. There's a long way to go."
White was Ryan's lead receiver, catching eight passes for 102 yards and a score.
The NFL's replacement officials, filling in for the referees during their lockout, had a tough game and seemed to lose control at times.
In the opening quarter a Broncos player came out of a pile seemingly having recovered a fumble, but the ball was awarded to the Falcons and several small skirmishes broke out.