Spínola entered the Colégio Militar in 1920, beginning what would be a very successful military career. By 1928 he had joined Portugal's Military Academy where he stood out as a young and promising cavalry officer.

In Lisbon, Anjos, in August 1932 he married Maria Helena Martin Monteiro de Barros (14 January 1913 - 23 May 2002), daughter of João de Azevedo Monteiro de Barros and his German wife Gertrud Elisabete Martin.

In 1939, he became adjunct-de-camp in the command of the Guarda Nacional Republicana (English: Republican National Guard). In 1941 he traveled to the Russian Front, as an observer, to monitor Wehrmacht movements during the encirclement of Leningrad, where Portuguese volunteers had been incorporated into the Blue Division.

In 1961, guided by António de Oliveira Salazar, he offered himself for voluntary service in Angola. In the command of the 345th Calvary Battalion he distinguished himself between 1961 and 1963. At the end of his tenure, he was nominated for and served as the Military Governor of Guinea-Bissau from 1968, and again in 1972, during the period of the Colonial War, where he favored a policy of respect for ethnic Guineans and the traditional authorities in the administration. At the same time, he continued to practice a range of initiatives in the War, from clandestine meetings (he met secretly with the President of Senegal Léopold Sédar Senghor at one point) to armed incursions to neighboring states (such as Operation Green Sea, which saw the assault by Portuguese Army Commandos into Conakry, Guinea).

In November 1973, he returned to Lisbon, on the invitation of Salazar's successor Marcello Caetano, to head the Overseas portfolio, which he refused due to the government's intransigence on the Portuguese colonies. A month later, on January 17, 1974, he was asked to be the Vice-Chief of the Defense Council of the Armed Forces, on the advise of Francisco da Costa Gomes, a post that he would be removed from in March. Shortly later, he would publish Portugal e o Futuro (English: Portugal and the Future), where he expressed the idea that the only solution to the Colonial Wars was the discontinuation of the conflict.

On April 25, 1974, as a representative in the MFA - Movimento das Forças Armadas (English: Movement of the Armed Forces) he received from the President of the Council of Ministers, Marcello Caetano, the rendition of the Government (which was in refuge in the Carmo Barracks). Although General Spínola did not play an important role, Marcelo Caetano insisted he would only surrender power to Spínola. This, ironically, allowed Spínola to assume an important public place as a leader of the revolution, although that was not what the MFA originally intended. The formation of the Junta de Salvação Nacional (English: National Salvation Junta), formed in the days following the Carnation Revolution, allowed Spínola to take on the role of President of the Republic.

Spínola met with Mobutu Sese Seko, the President of Zaire, on 15 September 1974 on Sal Island in the Cape Verde, crafting a plan to empower Holden Roberto of the National Liberation Front of Angola, Jonas Savimbi of UNITA, and Daniel Chipenda leader of the MPLA's eastern faction (a rival MPLA leader Agostinho Neto) while retaining the façade of national unity; Mobutu and Spínola wanted to diminish Neto importance and present Chipenda as the MPLA leader (Mobutu particularly preferring Chipenda to Neto because Chipenda supported autonomy for the Zairean province of Cabinda and Neto did not). The group also relied on the immense petroleum reserves of the Angolan exclave, estimated at around 300 million tons, which the Mobutu government required for economic survival.

Spínola lasted as the first post-Revolution President from May 15, 1974 until September 30 of the same year, to be substituted by General Francisco da Costa Gomes. His resignation partly due to what he saw as the profound move to the political left, their affects on the military and the independence of the Portuguese colonies; discontent over these changes he tried to intervene politically to mitigate the movements of the MFA program. He resigned fifteen days later on 30 September 1974, after just four months in power, when he realized he would not be able to block the application of the MFA program.

His appeals for the maioria silenciosa (English: silent majority) to resist the political radicalization of the left after the failed coup of September 28, 1974, or his tentative involvement in the rightist counter-revolution on March 11, 1975 (wherein he fled to Spain, then Brazil) were clear examples that Spínola had changed his allegiances. In the same year, he presided over the Exército de Libertação de Portugal (ELP), the Liberation Army of Portugal, a paramilitary terrorist group of the extreme-right. As the author Günter Wallraff wrote in his book Aufdeckung einer Verschwoerung - die Spínola Aktion, Spínola was always interested in returning to power and eliminating his political adversaries. During Spínola's exile to Brazil, he was approached by Wallraff who had infiltrated Spínola's group, pretending to be an arms dealer working for Franz-Josef Strauss, a conservative and leader of the Christian Social Union in Bavaria. Spínola's group was the MDLP - Movimento Democrático de Libertação de Portugal (English: Democractic Movement for the Liberation of Portugal) an anti-communist network of terrorist bombers, responsible for the death of a priest, and whose operatives included Carlos Paixão, Alfredo Vitorino, Valter dos Santos and Alcides Pereira. As their leader, Spínola had met with Wallraff to negotiate the purchase of arms and had supporters in the Alentejo, in order to regain power, which the author submitted as proof to the Swiss authorities to detain Spínola. But there was never enough proof to charge them in court.

But even his extreme swing would not affect his importance in the Carnation Revolution. In 1981 Spínola was promoted to the highest rank in the Army, Field Marshal. His prestige would be rehabilitated officially on February 5, 1987, by President Mário Soares, who bestowed on him the Grã-Cruz da Ordem Militar da Torre e Espada (English: Grand Cross of the Order of the Tower and Sword), for:

...his heroic military and civic service and for being a symbol of the April Revolution and first President of the Republic after the dictatorship...

On August 13, 1996, Spínola died at the age of 86, victim of a pulmonary embolism.

The mayor of the city of Lisbon, António Costa, marked the 100 years since António de Spínola's birth in a ceremony attended by President Cavaco Silva, which included the presentation of a plaque and naming of a new avenue in the capital.