Morkel has played 83 Tests for the Proteas taking 294 wickets.
He will aim to pass the 300 mark when the four-Test series gets underway on Thursday in Durban.
The 33-year-old has also starred in 117 ODIs and 44 T20 matches for South Africa, with 529 wickets across all three formats.
Morkel said: “It was an extremely tough decision but I feel the time is right to start a new chapter.
“I have to put them first and this decision will only benefit us going forward.
“I still feel there is a lot of cricket left in me and I am excited for what lies ahead.
“I have loved every minute that I have played in the Proteas jersey, and I am incredibly grateful to my team mates, Cricket South Africa, and my family and friends for the support over the years.
“For now, all of my energy and focus is on helping the Proteas win the upcoming series against Australia.”
Some of that cricket could be in England with Morkel potentially joining fellow South Africans Simon Harmer and Kyle Abbott as a Kolpak signing.
That would make him eligible to join one of the 18 counties in England and Wales while not classing as an overseas player.
He would be available for the start of the season having gone unsold in the recent Indian Premier League auction despite having previously played for Delhi Daredevils and Kolkata Knight Riders.
Morkel has experience playing in England, having had a spell at Kent in 2007 and Yorkshire a year later.