Makhlouf, who married late Syrian president Hafez al-Assad in 1957, rarely appeared in public even after al-Assad became president in 1971.
Al-Assad ruled Syria from 1971 until his death in 2000, and shared five children with Makhlouf, Bushra, Basil, Bashar, Majed and Maher.
Makhlouf was born in 1930 to a powerful and wealthy family from the coastal province of Latakia.
According to the Associated Press, "She was to prove a devoted wife and mother and Assad's closest and most trusted confidante, providing him with a domestic environment of unquestioned respectability," wrote Assad's late biographer Patrick Seale in his book "Asad: The Struggle for the Middle East."
Makhlouf is survived by her daughter Bushra and her two sons, Bashar and Maher Assad. Two other sons passed away, one of them, Basil, in a car accident in 1994, the Associated Press reports.
(Reporting by Lisa Barrington; Editing by Kevin Liffey)