Mustafa was born in the village of Prapashtica, in the Gollak Highlands of the District of Pristina, Kosovo on 15 May 1951, to Kosovo Albanian parents. He finished Primary and High School in Pristina, and attended the University of Pristina in the Faculty of Economics, where he obtained a master’s degree and a PhD. In 1974, he began his professional work, as an examiner at the University of Pristina.

After the Kosovo War ended on 1999, he returned home, but returned to politics only in 2006 as a High Political Advisor of the then President of Kosovo, Fatmir Sejdiu.

In December 2007, he became the mayor of Pristina in local elections, beating the vice president of the Democratic Party of Kosovo (PDK) and one of the ex-commanders of the Kosovo Liberation Army (UÇK), Fatmir Limaj. He won a second term as Mayor of Pristina in November 2009.

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.

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.

While addressing the Assembly of Kosovo on 22 September 2015 regarding an agreement with Serbia on autonomy for Kosovo’s ethnic Serb minority and another agreement defining the border between Kosovo and Montenegro, Mustafa was pelted with eggs by opposition Assembly lawmakers. He later continued his address while being shielded with an umbrella by his bodyguards.

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 July 10, 2020, Mustafa announced on his Facebook page that he was diagnosed with COVID-19. On August 1, 2020, he revealed on his Facebook page that he had fully recovered from the disease.