England coach Peter Moores confirmed Hampshire batsman Pietersen and Lancashire star Flintoff will be rested during September following the final one-day international against South Africa at Cardiff on Wednesday.
James Anderson, Ian Bell, Stuart Broad, Paul Collingwood and Ryan Sidebottom are the other five centrally contracted players who will recharge their batteries ahead of England's next competitive action - the Stanford Super Series in late October.
"It has been a gruelling summer schedule and it's important for those players involved in both the Test and ODI squads to be rested ahead of what promises to be a hectic winter," Moores said.
"With the postponement of the ICC Champions Trophy an invaluable break in the international schedule has emerged during September and it is important the players use that interval to refresh themselves mentally and physically ahead of a schedule that has little respite over the next 12 months.
"Those players involved in both England squads will be given a break from cricket but they will continue a comprehensive conditioning programme in preparation for the Stanford Super Series and the ensuing tour of India."
Durham fast bowler Steve Harmison is among those England players who are free to play for their counties over the coming weeks.
Harmison, who made his international comeback in August, is joined by Tim Ambrose, Ravi Bopara, Samit Patel, Monty Panesar, Matt Prior, Owais Shah, Andrew Strauss, Graeme Swann, Luke Wright.
Moores added: "We recognise that Stephen Harmison only featured in one Test match prior to joining England's ODI squad and as a result he will join Durham for the rest of the first-class season.
"Alastair Cook has not featured in the current NatWest Series and after working hard on his one-day game during recent weeks he is available for Essex's NatWest Pro40 match this Sunday and a Twenty20 floodlit challenge match on Friday."