Sayeed started his political career in the 1950s in the Democratic National Conference, a splinter group of the Jammu & Kashmir National Conference led by Ghulam Mohammed Sadiq. He was appointed as the district convenor of the party, which merged back into the National Conference in late 1960. In 1962, he was elected to the Legislative Assembly from Bijbehara. After G. M. Sadiq became the Chief Minister of the state in 1964, Sayeed was appointed as a Deputy Minister in his government. In January 1965, the National Conference merged into the Indian National Congress. Thus Sayeed became a member of Congress. In 1972, Sayeed became a cabinet minister and, the president of the state Congress unit. He is said to have brought about the downfall of the Jammu & Kashmir National Conference government, which was led by Farooq Abdullah, in 1984. He joined the Rajiv Gandhi government in 1986 as Minister of Tourism. In 1987, he quit the Congress party to join V. P. Singh's Jan Morcha, which led to his becoming the first Muslim Minister for Home Affairs in the Union Cabinet of India for one year, from 1989 to 1990. He rejoined the Congress under P. V. Narasimha Rao, which he left in 1999 along with daughter Mehbooba Mufti to form his own party, the Jammu and Kashmir Peoples Democratic Party.
In 1989, within few days of taking office as the Union Minister for Home Affairs, his third daughter, Rubaiya, was kidnapped. She was released in exchange for the release of five militants. During his tenure as Home Minister of India Exodus of Kashmiri Hindus took place.
Attacks on his family and himself
Besides attacks on family members Sayeed also survived attacks on his life by Kashmiri separatists. His daughter Rubaiya Sayeed was also kidnapped on 9 Dec 1989.
Death
On 24 December 2015, Sayeed was admitted to the AIIMS hospital in New Delhi. He suffered from neck pain and fever. His condition gradually deteriorated, and he was put on ventilator support. He died on 7 January 2016 due to multi-organ failure at about 7:30, according to provincial Education Minister and PDP Spokesman Nayeem Akhter. He was just five days short of his 80th birthday when he died. Reactions to this death came from Prime Minister Narendra Modi, national Home Minister Rajnath Singh at Delhi airport and the 14th Dalai Lama. He was buried at his ancestral burial ground in Bijbehera with state honours. Former Chief Ministers Omar Abdullah and Ghulam Nabi Azad were present at his funeral. Condolences also came from former President Pranab Mukherjee, former prime ministerial candidate L. K. Advani, Ram Madhav, Delhi Chief MinisterArvind Kejriwal, BJP Vice President Mukhtar Abbas Naqvi, former national Oil Minister Milind Deora, PDP member Rafi Mir and politicians Kalraj Mishra, Jitendra Singh and Ahmed Patel. According to party member and PDP Chief Spokesperson Mehboob Beg, the PDP supported his daughter, Mehbooba Mufti, as the next chief minister, while coalition ally BJP expressed "no objection" to her succeeding her father.