Spencer, who was a Pro Bowler with the Dallas Cowboys in 2012, will miss the rest of the season after suffering an unspecified injury that has kept him out since the first preseason game.
The Saints also placed cornerback P.J. Williams, a third-round draft pick from Florida State, on injured reserve with a hamstring injury. And they waived-injured receiver Nick Toon, safety Vinnie Sunseri and linebacker Ronald Powell among their other moves.
The 31-year-old Spencer, who signed with the Saints this summer to be reunited with defensive coordinator Rob Ryan, was never a sure thing to make the roster when he signed a one-year veteran-minimum deal in April. He hasn't been the same since suffering a major knee injury in 2013.
However, Spencer was making a good case for himself before he suffered the latest setback. He spent much of the summer working with the first-string defense and showed some nice flashes early in the preseason.
Spencer has 33 sacks over his eight-year career, including 11 in that Pro Bowl season.
The Saints, meanwhile, will count even more on a youth movement to fill depth at the edge rusher positions after also releasing embattled veteran Junior Galette this offseason.
The Saints are set at defensive end with former Pro Bowler Cameron Jordan, but they'll be counting on rookie second-round pick Hau'oli Kikaha, second-year undrafted edge rusher Kasim Edebali and rookie fifth-round pick Davis Tull to man the strongside linebacker position and other rotational pass-rushing spots in nickel and dime packages. Veteran linebacker/end Parys Haralson will also be in the mix.
Toon, a fourth-round draft choice out of Wisconsin in 2012 and the son of former NFL standout Al Toon, was never able to realize his potential in New Orleans. He had just 21 catches for 283 yards and a touchdown in 16 career games played.
Toon, 26, had his best opportunity yet to crack the rotation this summer. But he failed to capitalize on it, in part because of an ankle injury suffered during the second preseason game. Second-year pros Brandon Coleman and Willie Snead, and veterans Josh Morgan and Joe Morgan are battling for the Saints' top backup receiver jobs.