Born in Salerno, Martino was ordained as a priest in 1957. He holds a doctorate in Canon law and is fluent in Italian, English, French, Spanish, and Portuguese.
After finishing his studies, Martino entered the Vatican's diplomatic service in 1962, serving in Nicaragua, the Philippines, Lebanon, Canada, and Brazil.
In 1980, Martino was named apostolic pro-nuncio to Thailand and Singapore and apostolic delegate to Laos and Malaysia and was named Archbishop of the titular see of Segerme. In 1983, he was named apostolic delegate to Brunei Darussalam, while retaining his other posts.
In 1986, he was appointed Permanent Observer of the Holy See to the United Nations. He was on duty during the United States invasion of Panama, when president Noriega had taken refuge at the Vatican embassy.
In 1991, he opposed the American-led invasion of Iraq and was later critical of state sanctions against Iraq. In 1992, he participated at the UN Conference for the environment in Rio de Janeiro, speaking about the centrality of the human person.
In June 1994, Martino demanded at the UN that a "safe haven" be created for Tutsi refugees in Rwanda in order to save over 30 000 lives in Kabgayi.
In September 1994, he was the official spokesman for the Holy See at the International Conference on Population and Development.
Archbishop Martino was Pope John Paul II's official representative at the 1994 International Conference on Population and Development, and he had the task of defending the Church's pro-life teachings before a European-American bloc that strongly supported abortion on demand. Martino was able to find support from Latin-American and Arab countries that were anti-abortion, and the Cairo conference was ultimately inconclusive.
Later in 1995, he participated at the World Conference on Women in Beijing, echoing John Paul's positions in his letter to women. He has been on diplomatic mission to Côte d'Ivoire to settle disputes there.
On 1 October 2002, Martino was named President of the Pontifical Council for Justice and Peace.
In November 2003, he championed the use of genetically modified organisms (GMOs) to alleviate world hunger at a conference that he organized to consider the morality of GMOs, which troubled critics concerned about the risks they pose to the environment and heath.
Martino was elevated to the College of Cardinals in the consistory of 21 October 2003 becoming Cardinal-Deacon of S. Francesco di Paola ai Monti. Martino was one of the cardinal electors who participated in the 2005 papal conclave that selected Pope Benedict XVI.
In December 2003, reacting to U.S. treatment of Saddam Hussein, including the release of video showing his teeth being inspected "like a cow", he said: "I felt pity to see this man destroyed. Seeing him like this, a man in his tragedy, despite all the heavy blame he bears, I had a sense of compassion for him." On 6 November 2006, after Hussein had been sentenced to death, Martino said that "...punishing a crime with another crime – which is what killing for vengeance is – would mean that we are still at the point of demanding an eye for an eye, a tooth for a tooth..." He pleaded for clemency for Hussein and called for a peace conference aimed at solving all the major conflicts in the Middle East and reiterated his position that invasion of Iraq by U.S.-led coalition was wrong.
Martino was named President of the Pontifical Council for the Pastoral Care of Migrants and Itinerants on 11 March 2006.
In November 2006, Martino call plans by the Bush administration to construct an additional 700 miles of fencing along the U.S.-Mexico border "an inhumane program". He also said that Muslims in Europe should respect local laws restricting the wearing of certain types of veils. He said: "It seems elementary to me and it is quite right that the authorities demand it." He said they "must respect the traditions, symbols, culture and religion of the countries they move to".
On 14 June 2007, Martino urged Catholics to withhold donations from Amnesty International after the organization decided in April to advocate support access to abortion in cases where pregnancy threatened a woman's life or was the result of rape or incest.
Speaking on the 2008–2009 Israel–Gaza conflict Cardinal Martino said that "Defenseless populations are always the ones who pay. Look at the conditions in Gaza: more and more, it resembles a big concentration camp." He called for peace talks: "If they can't come to an agreement, then someone else should do it (for them). The world cannot sit back and watch without doing anything. We Christians are not the only ones to call this land 'holy', Jews and Muslims do so too. The fact that this land is the scene of bloodshed seems a great tragedy." When the Israeli Foreign Ministry objected to the use of the phrase concentration camp, Vatican officials distanced themselves from Martino's remarks. Elaborating on his remarks, he said: "I say that the conditions people are living in there should be looked at: surrounded by a wall that is difficult to cross, in conditions contrary to human dignity. What is happening during these days is horrible. But when I speak, may people take into account the whole of what I say." He said both sides are "guilty" and that it is "necessary to separate them, like two fighting siblings" and make them "sit down to negotiate".
Cardinal Martino has taken a great interest in automobiles and has proclaimed the Ten Commandments for Drivers. He has collaborated with the Fédération Internationale de l'Automobile.
Cardinal Martino submitted his resignation as required when he reached the age of 75. On 28 February 2009, Pope Benedict relieved Cardinal Martino of the presidency of the Pontifical Council for Pastoral Care of Migrants and Itinerant Peoples, appointing Archbishop Antonio Maria Vegliò to succeed him. On 24 October 2009, Pope Benedict named Cardinal Peter Turkson to succeed Martino as president of the Pontifical Council for Justice and Peace.
In July 2010, Cardinal Martino assumed the position of Honorary President of the Dignitatis Humanae Institute, a Rome-based organisation established to promote human dignity "based on the recognition that man is made in the image and likeness of God".
In November 2010 Cardinal Martino was appointed by Prince Carlo, Duke of Castro as Grand Prior of the Sacred Military Constantinian Order of Saint George. On 25 June 2012 Prince Carlo, Duke of Castro appointed him Knight of the Illustrious Royal Order of Saint Januarius.
On 8 October 2011, he was named special papal envoy to the celebration of the centenary of the cathedral of Yangon, Burma, programmed for 8 December 2011. Cardinal Martino was to meet Nobel peace laureate Suu Kyi, a Buddhist, who was to be in attendance. Representatives of all religions in Burma, where Catholics represent only around one percent of the population, were invited to the event, when Martino was to read a message from Pope Benedict XVI. The envoy was then to have lunch with local clergy and "special guests". The pope called on Martino to transmit "a message of goodwill" to political and religious authorities in Myanmar, where the military dictatorship has made a number of gestures of greater openness in recent months.
Though he was too old to participate in the 2013 conclave that elected Pope Francis, Martino was one of the six cardinals who made the public act of obedience on behalf of the College of Cardinals to the new pope at his papal inauguration.
On 12 June 2014, Martino became the longest serving cardinal deacon following the elevation of Cardinal Jean-Louis Tauran to the rank of Cardinal-Priest. Cardinal Martino had declined the title of Cardinal-Priest and as the senior cardinal deacon succeded Tauran as Protodeacon.
In letters dated 21st July 2017, the Governor-General of Antigua and Barbuda issued notice that Martino's 2014 appointment to the Order of the Nation (Antigua and Barbuda) had been annulled.