The Gloucester full-back has suffered a torn calf muscle, prompting a recall for Northampton wing Ben Cohen.
Cohen, who has amassed 31 Test tries was initially left out of the side, but he now returns in the No 11 shirt, with Josh Lewsey switching to 15.
It means Cohen will have started all three autumn Tests, and will not be available to face the Springboks next week.
An agreement between England and Premier Rugby stipulates no player is allowed to start more than three of the four autumn games.
Cohen needs one more touchdown to move above Will Greenwood into second place on England's all-time try list, with only Rory Underwood ahead of him.
For 27-year-old World Cup winner Balshaw, it is the latest setback during an injury-hit career.
He joined Gloucester from Leeds earlier this year and, after making a Guinness Premiership debut against former club Bath in September, an ankle injury then sidelined him for several weeks.
Lewsey though, is a high-class replacement, with England now fielding comfortably their most experienced back three unit of an autumn schedule that has so far produced defeats against New Zealand and Argentina.