Husseini was born in Baghdad son of Abd al-Qadir al-Husayni, commander of local Arab forces during the siege of 1948 and grandnephew of the Haj Mohammad Amin al-Husayni, the former Grand Mufti of Jerusalem. He studied in Cairo, Baghdad, and Damascus. He was a founding member of the General Union of Palestinian Students (GUPS) in 1959.
Husseini went to work for the Palestine Liberation Organization (PLO) upon its establishment in Jerusalem as deputy manager of the Public Organisation Dept, a post he filled from 1964 to 1965. He later received military training at the Damascus Military College after which he joined the Palestinian Liberation Army in 1967.
In 1979, Husseini founded and became chairman of the Arab Studies Society.
From 1982–1987, he was repeatedly placed under house and city arrest. He was imprisoned several times from April 1987–January 1989, but remained active in the Intifada.
In 1982, he became a member of the Supreme Muslim Council in Jerusalem. Subsequently he served as a Palestinian spokesperson, head of the Jerusalem National Council/Palestine, member and later head of the Palestinian delegation to the Madrid Middle East Peace Conference and subsequent talks, head of the Fatah faction in the West Bank, and Palestinian Authority Minister without Portfolio.
His last post was Palestinian Authority Minister for Jerusalem Affairs for which he was based in East Jerusalem. He died while trying to mend relations between the Kuwaiti government and PLO which were broken at the time of the 1991 Gulf War.
Husseini was considered a pragmatist by journalists. He taught himself to speak Hebrew and regularly appeared in radio and television shows in Israel to explain the Palestinians' point of view.
Husseini was buried on the Temple Mount, Judaism's holiest site and a Muslim holy site as well. Right-wing Jews see the burial as an insult, for Jewish purity laws forbid dead bodies from the Temple Mount.
Following Husseini's death, Israeli police seized his headquarters, the Orient House.
Authorities are now reexamining the death of Husseini, who died in his Kuwait hotel room. This was sparked by the suspicious death of Hamas military commander Mahmoud al-Mabhouh.