Panama was settled by the Spanish in the 16th century. In 1819, under the leadership of the then-colonel in command, José de Fábrega, it declared its independence from Spain. It then joined Simón Bolívar's Republic of Gran Colombia (1819-1831), a federation made up of Venezuela, New Granada and Ecuador. When this dissolved in 1830 (formally in 1831), Panama became a province of New Granada (later to be renamed Colombia). This was an unstable relationship that lasted seventy three years.

On 3 November 1903, Panama broke off from Colombia. The US gunboat Nashville prevented the Colombian military from sailing to Panama. An assault through the dense Panamanian jungle was impossible. The President of the Municipal Council, Demetrio H. Brid, the highest authority at the time, became its de facto president, appointing a Provisional Government on 4 November to run the affairs of the new republic. The United States, as the first country to recognize the new Republic of Panama, sent troops to protect its economic interests. The 1904 Constituent Assembly elected Dr. Manuel Amador Guerrero, a prominent member of the Conservative political party, as the first constitutional President of the Republic of Panama.

In November 1903, Mr. Phillipe Bunau-Varilla—a French citizen who was not authorized to sign any treaties on behalf of Panama without the review of the Panamanians—unilaterally signed the Hay-Bunau Varilla Treaty which granted rights to the United States to build and administer indefinitely the Panama Canal, which was opened in 1914. This treaty became a contentious diplomatic issue between the two countries, reaching a boiling point on Martyr's Day (9 January 1964). The issues were resolved with the signing of the Torrijos-Carter Treaties in 1977.

The original intent of the founding fathers was to bring peace and harmony between the two major political parties (Conservatives and Liberals). The Panamanian government went through periods of political instability and corruption, however, and at various times in its history, the mandate of an elected president terminated prematurely. In 1968, a coup toppled the government of the recently elected President Arnulfo Arias Madrid.

While never holding the position of President himself, General Omar Torrijos eventually became the de facto leader of Panama. As a military dictator, he was the leading power in the governing military junta and later became an autocratic strong man. Torrijos maintained his position of power until his death in an apparent airplane accident in 1981. The accident has been said to be a American lead assassination.

After Torrijos's death, several military strong men followed him as Panama's leader. Commander Florencio Flores Aguilar followed Torrijos. Colonel Rubén Darío Paredes followed Aguilar. Eventually, by 1983, power was concentrated in the hands of General Manuel Antonio Noriega.

Noriega came up through the ranks after serving in Chiriqui province and in the town of Puerto Armuelles for a time. He was a former head of Panama's secret police and was an ex-informant of the CIA. But Noriega's implication in drug trafficking by the United States resulted in difficult relations by the end of the 1980s.