The 31-year-old sustained a hip problem during her side’s six-wicket victory over the Proteas in the first T20 at Chelmsford on Thursday.
Knight is being assessed and treated for the injury, with vice-captain Nat Sciver taking charge of the side for the clash at New Road.
Alice Capsey was brought in for Knight with the 17-year-old set to make her international debut, having recently been named in England’s Commonwealth Games squad.
England will be hoping their captain makes a quick recovery in time for the start of the Birmingham Games, with their first match against Sri Lanka on July 30.
England have already wrapped up victory in the multi-format series against South Africa following their win at Essex and go into Saturday’s match with 10-2 lead, having also won all three one-day internationals following a draw in the standalone Test match.