Smith, the longest-tenured player on the Saints' roster, injured his knee in a preseason game against the Houston Texans, and on Monday was diagnosed with an ACL tear.
Previously a regular defensive end, Smith moved to outside linebacker under defensive coordinator Rob Ryan who changed the system from a 4-3 to a 3-4 in 2013.
Ryan is losing several players to injury, including Smith's fellow outside linebacker Victor Butler, who suffered his own season-ending knee injury earlier this summer.
Also this summer, veteran defensive end Kenyon Coleman suffered a season-ending pectoral injury, and a lingering knee injury may soon bring down veteran linebacker Jonathan Vilma after another setback earlier this month.
In search of immediate help in the wake of the injuries, the Saints acquired Parys Haralson, formerly of the San Francisco 49ers.