Berisha was born in Viçidol, Tropojë District, Kukës County, northern Albania, near the border with Kosovo to a Muslim father and mother: Ramë and Sheqere Berisha. He studied medicine at the University of Tirana, graduating in 1967. He specialized in cardiology and was subsequently appointed as an assistant professor of medicine at the same university and as staff cardiologist at the Tirana General Hospital. At the same time, Berisha became a member of a discussion forum for changes in the Albanian Party of Labor while having been enrolled as a member a few years earlier. During the 1970s, Berisha gained distinction as the leading researcher in the field of cardiology in Albania and became professor of cardiology at the University of Tirana. In 1978 he received a United Nations Educational Scientific and Cultural (UNESCO) fellowship for nine months of advanced study and training in Paris. He also conducted a research program on hemodynamics that attracted considerable attention among his colleagues in Europe. In 1986 he was elected to be a member of the European Committee for Research on Medical Sciences, where he worked for the elaboration of scientific researches strategies for “Health for all”.

In an article published in the Bashkimi newspaper on 17 September 1990, Berisha condemned what he termed the “cosmetic reforms” of the Alia regime, which had only served to aggravate unrest within the nation. Without political pluralism, he argued, there could be no true democracy in Albania.

In December 1990, Berisha joined, on the very first day, a series of student demonstrations that forced the government to approve the establishment of a multi-party system. Berisha emerged as the leader of the Democratic Party of Albania (DP), the first and largest of the new opposition parties. All leading members of the party wore white coats during demonstrations. He was formally elected DP chairman in February 1991 at the party’s first national congress. He was elected member of Albania parliament in 1991, 1992, 1997, 2001 from the constituency of Kavajë.

After the 1992 elections—the first free legislative elections held in the country in decades—Berisha was elected president on 9 April 1992. He was the country’s first freely elected head of state, and the first non-Communist head of state in 53 years.

Following his election, Berisha and his government were engaged in a profound course of political, economic, institutional, legislative and multifaceted reforms. Therefore, the complete privatization of land and residencies, as well as of all small and medium state enterprises, was accomplished over the period 1992–96; prices and exchange rates were fully liberalized, and Albania changed from a country of a three figure inflation rate and economic growth regression of −20% into a country with a one-figure inflation rate and with an average economic growth rate of 9% in 1992 and, in ’93 – ’96, 75% of GDP was generated from the private sector. Albania opened towards the West; it became a member of the Council of Europe in 1995; it signed the Partnership for Peace Agreement in 1993, and it established a close cooperation with European Union countries and the United States.

During the first ten days of March, the situation deteriorated, culminating in the desertion of large numbers of police and military, leaving their arsenals unlocked. These were promptly looted, mostly by militias and some criminal gangs, and for a time it looked like civil war would erupt between the government and rebels. Although the Prime Minister resigned immediately, Berisha refused opposition demands to step down, claiming he had to ensure continuity, and UN and European Multinational Forces were required to step in and take the situation under control. After their intervention in Albania, early elections were held in June 1997, leading to the victory of a socialist-led coalition of parties. On 24 July 1997, a month after the DP lost the 1997 elections to the left coalition, Berisha stepped down as president and was replaced by the socialist Rexhep Meidani. In 1997 he became the chairman of the Democratic Party, which became the biggest opposition party. He eventually returned to power as Prime Minister between 2005 and 2013.

The murder of DP MP Azem Hajdari on 12 September 1998, triggered two days of violent protests in Tirana. During Hajdari’s funeral procession on 14 September 1998, armed DP supporters ransacked government offices, and for a brief period, held the PM’s office, the parliament building, and the Albanian State television and radio building. Estimates of casualties during the protests and riots ranged between 3 and 7 deaths and 14 and 76 injuries. After 72 hours, the Government restored order and reclaimed tanks and armored personnel carriers seized by DP supporters that were being held at the Democratic Party main offices in Tirana. Parliament subsequently lifted Berisha’s immunity due to his alleged role in what the government described as a coup d’état, but no charges were laid. Berisha blamed the Socialist Party of Albania and its leaders for the murder. Twelve people were arrested for their alleged involvement in the violence. In February 2002 five people, including Jaho Mulosmani, were sentenced for the murder by a Tirana district court.

Sali Berisha led the coalition of the center-right parties in the general elections held in five rounds in June–August 2001. Although Organization for Security and Co-operation in Europe/ODIHR International Election Observation Mission declared these elections as being manipulated. The coalition won 37% of the votes. Berisha led continuous peaceful demonstrations demanding fresh elections.

On 3 July 2005, Sali Berisha was able to lead a coalition of five right center parties into the 2005 parliamentary elections, which eventually won a majority of 74 MPs from a total of 140. He was appointed Prime Minister of Albania on 8 September 2005.

On 10 June 2007, Sali Berisha met with U.S. President George W. Bush in Tirana. Bush became the first U.S. president to visit Albania and repeated his staunch support for the independence of neighbouring Kosovo from Serbia: “At some point in time, sooner rather than later, you’ve got to say, enough is enough. Kosovo is independent.”

On 15 March 2008, Berisha faced the toughest challenge of his government when an ammunition dump exploded in the village of Gërdec near Tirana, causing the deaths of 26 people and injuring over 100. Defense Minister Fatmir Mediu resigned, and the press reported many irregularities at the blast site, operated by an Albanian company that deactivated the country’s aging ammunition and then sold it for scrap.

In June 2009, Berisha’s Democrats declared a narrow win in the parliamentary elections. Berisha’s alliance came up one seat short of a majority and had to join forces with a splinter socialist party, the Socialist Movement for Integration of Ilir Meta, in order to retain power. Berisha appointed to Meta to the post of Deputy Prime Minister for Foreign Affairs, and later Minister of Economy, Trade and Energy. It is the first time since the start of multi-party democracy in 1991 that a ruling party had been forced into a coalition through not winning enough seats on its own.

The 2009 elections were flawed and have been called as such by the socialist opposition, who have asked for a recount of the ballots. Berisha refused any recount of the votes, on the grounds that the Albanian Constitution does not foresee such procedure. For that reason he called the opposition to the parliament to change the constitution, but the Socialist Party refused. The political crisis between government and opposition worsened over time, with the Socialists abandoning parliamentary debates for months and staging hunger strikes to ask for internal and international support. The EU attempted a conciliation, which failed. The ongoing political crisis was one of the reasons for the EU’s refusal to grant Albania official candidate status in late 2010.

On 21 January 2011, clashes broke out between police and protesters in an anti-government rally in front of the Government building in Tirana. Four people were shot dead from government special forces. The EU issued a statement to Albanian politicians, warning both sides to refrain from violence, while Berisha defined the protests and the subsequent charges by judges upon policemen as stages of an attempted coup against him – consequently using this to his advantage to further attempt to consolidate his grip on the state institutions. He accused the then President of having been part of the coup after the relations had soured between the two and he embraced his perceived victim status to install his own ‘yes man’ in the office.

Under his leadership, Albania made several strides in sustainable development. In the 2012 Environmental Performance Index, the country ranked 4th out of 132 countries, while maintaining an average GDP growth of 5.1% between 2007 and 2011. BY 2012, the country was producing more than 96 percent of the energy through renewable hydropower resources. For his significant achievements and contributions to sustainable development, he was awarded the Fray International Sustainability Award in 2012.

After his party’s defeat in the 2013 parliamentary election, Berisha resigned as party leader, but he remained in parliament.