The second-year pro, who had won his previous two starts, completed just 6 of 19 passes for 99 yards and three interceptions in the team's 23-7 loss to the 49ers, and was pulled from the game in the fourth quarter.
A step back in his progression? Hard to say it wasn't.
"After what he's done the last couple weeks where you saw he was making progress, it's frustrating," Cardinals head coach Ken Whisenhunt said. "I know it's frustrating for John, but he's a young player -- that happens with young players.
"We've got to get him through this, we've got to get better at making sure that he won't, hopefully, struggle."
That's because, as Whisenhunt said, starting quarterback Kevin Kolb wasn't really close to playing Sunday. There is no timetable for his return, meaning Skelton may be in line for another start Sunday in St. Louis.
"John didn't play his best [Sunday], but he's got to bounce back and if he has to play this week he's got to be ready to go," Whisenhunt said.
Arizona Sports' Kyndra de St. Aubin contributed to this report