King Zwelithini had been in hospital for weeks for what was initially reported to be a problem with his blood glucose levels.
The royal house said his health took a turn for the worst and he passed away in the early hours of Friday morning.
They’ve also thanked South Africans for their prayers and support during his illness.
“On behalf of the Royal Family, we thank the nation for your continued prayers and support in this most difficult time,” the statement read.
He was 72 years old.
King Zwelithini made history as the longest serving monarch of the Zulu Kingdom – with a reign spanning over five decades.
Born on 14 July 1948 in Nongoma, northern KwaZulu-Natal, he’s the eldest son of King Cyprian Bhekuzulu and his second wife Queen Thomo.
Following his father’s passing in 1968, King Zwelithini was appointed to the throne – he was just a 20-year-old student at the time.
But he was not crowned until 1971 because he had to go into hiding outside the kingdom following a plot to have him killed