The 29-year-old - the Falcons' joint-top touchdown scorer with five - suffered the injury during the fourth quarter of his side's 19-17 victory over the Carolina Panthers on Sunday.
Smith, who is in the final year of his contract, joins a long list of Falcons players on the season-ending injured reserve list, with the likes of Sean Weatherspoon (Achilles), Sam Baker and Joe Hawley (both knee) already sidelined.
A post on the Falcons' official website read: "Running back Antone Smith has a broken leg and will be placed on season-ending injured reserve.
"Smith was injured on a special teams play in Sunday's win over Carolina."
In addition to Smith's injury, the Falcons also confirmed cornerback Robert Alford would miss up to a month with a wrist complaint, with Robert McClain expected to step in.
The Falcons currently sit top of the NFC South.