He was the closest associate of al-Sadr in the leadership of Amal, serving as head of its political wing, as well as in the Supreme Islamic Shia Council, which he had become a founding member of in 1967.

He resigned from this post on 17 June 1980, following a failed assassination attempt on his life by PLO militants and after resisting pressure from Syria to engage Amal in the Lebanese Civil War.

In 1989, while in office, el-Husseini orchestrated and presided over the Taif Agreement, held in the Kingdom of Saudi Arabia, which led to the end of the Lebanese Civil War (1975–1990).

In 1992, Berri was backed by the Syrians during their military presence in Lebanon to replace Husseini as Speaker, as Husseini had refused, despite enormous pressure, to pass a law that would allow Rafic Hariri (and later Solidere) to expropriate land and property in the Beirut Central District and compensate owners with shares in the company worth as little as 15% of the property's value.

On 12 August 2008, in a speech during the vote of confidence for the new government, Husseini announced his resignation from parliament, expressing his fury at how the constitution was being torn.

[14] Nicknamed Abu t-Taif (Father of the Taif Agreement) or ʿArrab at-Taif (Godfather of the Taif Agreement) for his role in fathering the peace accords that ended the Lebanese Civil War, el-Husseini was strongly and actively opposed to Lebanon's sectarian political system, and was a leading critic of Lebanon's post-war Hariri-led governments' economic and fiscal policies that eventually led to the Lebanese liquidity crisis, which became apparent in 2019.

[19] Palestinian historian Tarif Khalidi wrote of him: The “Sayyid” embodied in his person true patriotism, was a maker of his country’s constitution and loyal to it, well-versed in his knowledge of its laws and legislation, insightful into the higher interests of his country, majestic, dignified, wise, fair in presiding over his parliament, skilled in his speech and logic.