Smith's struggles were predictable in his first career start. The former Utah star never got comfortable, going 9-of-23 for 74 yards and committing five turnovers while getting sacked five times.
"Everyone wants to win their first game, and everyone wants it to be just like college, but it's not," Manning said. "It is the NFL for a reason. It's a big adjustment. It's tough going against an excellent defense in your first start. ... Six games or a year from now, you look back on these games and you say, 'I hated to go through it, but it helped me become a better player.'"
Manning went 23-of-31 for 255 yards and one score, throwing two interceptions in an unimpressive performance against a team that gave significant playing time in its secondary to three recent practice squad members.
The reigning league MVP also failed to hook up with Marvin Harrison for the duo's 86th touchdown, which would have broken the NFL record shared with San Francisco's Steve Young and Jerry Rice.
But the Colts scored two fourth-quarter touchdowns on James' 4-yard run and Troy Walters' 18-yard reception to blow it open. Cato June returned one of his two interceptions 24 yards for a score in the second quarter, and Dominic Rhodes rushed for an early TD.
"You love everything to be perfect, but they made a few plays and we worked through it and got a good win on the road," said Manning, who started his 117th straight game to break his tie with Ron Jaworski for the second-longest streak in NFL history. "That is what good teams do. The idea was just to take care of business, and we did that."
Indianapolis (5-0) still won easily because its inconsistencies were nothing compared to the travails of Smith, promoted to the starting lineup after a month of mediocrity from Tim Rattay.
"I think they were reading a rookie quarterback's eyes, and a few times I gave myself away," Smith said. "I've got to learn when to force some things, and when to throw things away. I talked to Peyton (afterward), and he says it's going to get better."
In its fourth straight loss, San Francisco (1-4) failed to score an offensive touchdown for the second straight game despite a rare impressive performance from Kevan Barlow, who rushed for 99 yards.
Smith's headset apparently malfunctioned on the opening drive, and things never got much better. He had three interceptions, was sacked twice and fumbled once in the first half. His quarterback rating dropped to 4.4 when Mike Doss intercepted his pass into triple coverage 1:04 before halftime.
"He made some throws that I'm sure he won't make this time next year," Indianapolis coach Tony Dungy said. "I think Alex is going to be good. I coached against John Elway in his first game, and it was very similar. You can't judge anyone by their first game."