Koussa worked as a security specialist for Libyan embassies in Europe before
being appointed as Libya's Ambassador to the United Kingdom in 1980. He was expelled from the United Kingdom in 1980, after stating in an interview with The Times newspaper that his government intended to eliminate two political opponents of the Libyan government, who were living in the UK.
Later he served as Deputy Minister of Foreign Affairs from 1992 to 1994 and as the head of theLibyan intelligence agency from 1994 to 2009. He was a key figure in the normalization of relations between Libya and many NATO nations, including the United States and the United Kingdom. Koussa was key in securing the release of Pan Am Flight 103 bomber Abdelbaset al-Megrahi. In October 2008, he met both British and Scottish government officials, listed as an interpreter. In a second visit in January 2009, he was listed as Minister of Security.
On 4 March 2009, Koussa was designated as Minister of Foreign Affairs, replacing Abdel Rahman Shalgham, in a ministerial reshuffle announced by the Libyan parliament.
In an interview published by Asharq Al-Awsat on 10 November 2009, Koussa sharply criticized some aspects of Chinese investment in Africa. According to Koussa, it was unacceptable for the Chinese to bring "thousands of Chinese workers to Africa" when Africans themselves needed jobs, and he spoke of "a Chinese invasion of the African continent" that he said "brings to mind the effects that colonialism had on the African continent". Koussa also harshly criticized China's unwillingness to deal with the African Union and its preference for dealing with individual African states, which he said was suggestive of a divide and rule policy. Furthermore, he stressed the importance of political cooperation in addition to economic cooperation, saying that the former was lacking in China's relationship with Africa. He said that China only dealt in business, and never engaged in political support, in order to please all sides in a dispute.
Koussa was described as "hands shaking" as he announced a ceasefire weeks into the 2011 uprising, after the UN Security Council had opened the way to a no-fly zone. Western "officials indicated that they were prepared to move quickly if a decision was made to take military action. France and the UK and then the United States responded [to the ceasefire announcement] with almost identically worded skepticism ...." Attacks by government troops on Benghazi were also being reported – and denied – at the time, some hours after the announced ceasefire.