The controversial quarterback sustained a hamstring problem against the Carolina Panthers, rendering his 2014-15 campaign complete - with the Browns' record of 7-8 putting them out of play-off contention.
Browns head coach Mike Pettine announced on Monday that Manziel will sit out the Browns' last game.
Manziel was injured in the second quarter of the Browns' 17-13 loss to the Panthers.
Pettine said Manziel's first season with the Browns, which saw him play about seven quarters on the field, was positive enough.
"It's a several-week injury," Pettine said on a conference call with reporters.
"It is unfortunate he got hurt... I thought he did make strides in his rookie season. [He] had a big learning curve with system change."
Manziel finished his rookie season completing 18-of-35 pass attempts for 175 yards with zero touchdowns and two interceptions. He rushed for 29 yards and one touchdown.
With Brian Hoyer suffering a shoulder injury in the Panthers game, the Browns are expected to activate Connor Shaw, an undrafted free agent from South Carolina, off the practice squad.
"If he does have to play, I wouldn't be surprised if he plays well," Pettine said of Shaw.
"[He has] that 'it' factor. He found a way [in college]. He's well respected by his teammates. He works his tail off.''
If Shaw does start, it would mark the fifth season in a row that a third-string quarterback starts the Browns' 16th game of the season.
The Browns can eliminate American Football Conference North rivals Baltimore (9-6) from play-off contention with a win on Sunday.