The Reds' ace, who lasted just eight pitches in Game 1 Saturday because of back spasms, was pulled before Game 4 because of pulled muscles in his side, the Los Angeles Times and MLB.com reported.
Cueto, 26, who went 19-9 with a 2.78 ERA during the regular season, will also miss the NL championship series if Cincinnati, which leads the best-of-five division series 2-1, makes it that far.
The Giants avoided elimination Tuesday with a 10-inning 2-1 win over the Reds, who lead the best-of-five NLDS series 2-games-to-1.
"It was a very, very tough decision to make," General Manager Walt Jocketty said. "But our medical staff felt at best, Johnny would be able to pitch maybe one game in the next series if we get there, if he were available for that series."
Right-hander Mike Leake was to replace Cueto on the mound Wednesday.
Leake was 8-9 with a 4.58 ERA in 30 starts this season.
"It's quite a blow, but at the same time, you hope Leake steps up and pitches well," Manager Dusty Baker said.