The 33-year-old is renowned for generating steep bounce from a tall, wiry frame and has taken 529 wickets across all three formats since making his Proteas debut in the 2006 Boxing Day Test against India.
Morkel has an opportunity to become only the fifth South African - after Shaun Pollock, Dale Steyn, Makhaya Ntini and Allan Donald - to reach 300 Test wickets in the next few weeks, having so far taken 294 scalps at an average of 28.08.
However, the four Tests against Australia, the first of which begins on Thursday in Durban, will be his last in a South Africa shirt.
Morkel said: "It was an extremely tough decision but I feel the time is right to start a new chapter.
"I have a young family and a foreign wife, and the current demanding international schedule has put a lot of strain on us. I have to put them first and this decision will only benefit us going forward.
"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."
Morkel, who has featured in 83 Tests, 117 one-dayers and 44 Twenty20s for his country, has no intention of retiring from playing altogether.
That raises the possibility of him joining a number of other former South Africa internationals in signing for an English county side on a Kolpak deal this year.
He added: "I still feel there is a lot of cricket left in me and I am excited for what lies ahead. For now, all of my energy and focus is on helping the Proteas win the upcoming series against Australia."
Morkel, whose elder brother Albie also played for South Africa, had a prominent role in the side that rose to the top of the International Cricket Council rankings six years ago.
Thabang Moroe, Cricket South Africa's acting chief executive, said of Morkel: "He has formed part of the golden era of fast bowlers that have made the South African Test team a champion outfit that is respected throughout the world.
"Being a champion fast bowler is one of the most difficult professions in the sporting world.
"It requires tremendous skill, dedication and perseverance and, by no means the least, the courage to bowl through the pain barrier at times. Those are characteristics Morne has shown throughout his career."
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