The 49ers All-Pro outside linebacker and veteran wide receiver were slated to dress for the team in its Sunday matinee with the visiting Carolina Panthers.
Smith, who last played in Week 3, had been absent from the team since Sept. 23.
Manningham would be making his season debut. The wideout was rehabbing from surgery on his left knee.
Also inactive for the 49ers were quarterback
San Francisco did make room to keep running back/returner
Not suiting up for the Panthers: wide receivers Tavarres King, Marvin McNutt, cornerbacks Josh Norman and James Dockery, offensive guard Chris Scott, tight end Brandon Williams and defensive end Wes Horton.