Drew Brees continues to rewrite the NFL record books.
However, his hold on the record may be tenuous, as Tom Brady is third on the list with 538.
Smith appeared to catch Brees' third of the game just before halftime, but the play - and celebration - was called off due to an offensive pass interference penalty.
On the Saints' first drive of the second half, Brees marched down the field and found tight end Josh Hill in the end zone for a 5-yard score and the record-breaking 540th touchdown pass of his career.
Taysom Hill was the recipient of the fourth touchdown, a 28-yard score.
The record-breaking play came on the same evening the Saints were celebrating their 2009 championship-winning team, which beat the Colts in Super Bowl XLIV.
Brees topped Manning, a Louisiana native, while playing against the retired passer's former team.
The 40-year-old also owns the most passing yards in league history and the record for completion percentage in a season.
Brees also set a new record for completion percentage in a game by going 29 of 30 for 307 yards on the night.