Isa Mustafa began his political career in the early 1980s, when he became the head of the municipal government of Pristina, from 1984 to 1988.[1] In the 1990s, as Yugoslavia started to break up, Mustafa became the Minister of Economy and Finances of the government of the Republic of Kosova, in exile, headed by Bujar Bukoshi.[1] During this time, an arrest warrant for Mustafa was issued within Yugoslavia – which did not become international, making it possible for him to work in Western Europe. Mustafa did not apply for any political asylum, and was able to return to Kosovo anytime if needed.[1]
On 7 November 2010, he became the leader of the Democratic League of Kosovo, beating Fatmir Sejdiu in the party leadership election by 235 votes to 124.[3]
On 1 December 2013, he lost re-election to the position of Mayor of Pristina, in what was seen as a major upset, to upcoming politician Shpend Ahmeti. The upset was especially dramatic seeing as it happened in what had been historically known as a Democratic League of Kosovo stronghold.
On 8 December 2014, he became the Prime Minister of Kosovo in a coalition with the Democratic Party of Kosovo. With a PhD in Economics, he claimed his government would be focused on the economic development of the country.
On 10 May 2017, Mustafa lost a vote of no-confidence and decided not to stand in the next election. Instead he nominated Avdullah Hoti as the Democratic League candidate for prime minister. Mustafa stayed on as Prime Minister until his successor Ramush Haradinaj was elected by parliament in September 2017 following a parliamentary election.
On 3 August 2019, Isa Mustafa was re-elected as leader of the Democratic League of Kosovo for the third time.
On 10 July 2020, Mustafa announced on his Facebook page that he was diagnosed with COVID-19.[5] On 1 August 2020, he revealed on his Facebook page that he had fully recovered from the disease.
On 15 February 2021, Mustafa announced he would be standing down as the leader of the Democratic League of Kosovo after a poor result in the 2021 elections. He officially resigned at the LDK convention on 14 March 2021, and was succeeded by Lumir Abdixhiku, who named Mustafa as the honorary president of LDK the same day.