Christodoulos, who headed the church for a decade, was first hospitalized in Athens in June before being diagnosed with cancer of the liver and large intestine.
He spent 10 weeks in a hospital in Miami but an October liver transplant operation was canceled when doctors discovered the cancer had spread. He refused hospital treatment in the final weeks of his life. He died at his home in the Athens suburb of Psyhico, church officials said.
The Interior Ministry announced four days of national mourning and said Christodoulos would be buried on Thursday with full state honors. Across the country flags flew at half-staff, including atop the ancient Acropolis and on the parliament building.
The archbishop's flag-draped coffin was taken to the cathedral in Athens, where his body will lie in state until his funeral. Hundreds of people began gathering outside to pay their respects.
Christodoulos was elected church leader in 1998 and is credited with reinvigorating the vast institution that represents 97 percent of Greece's native born population.
He was one of several leaders of national Orthodox churches across the world. Istanbul-based Ecumenical Patriarch Bartholomew I is the spiritual leader of the world's 250 million Orthodox Christians.
Christodoulos helped create church Web sites and radio stations, and frequently issued detailed checklists on how black-clad Orthodox priests should conduct themselves in public.
In 2001, Christodoulos received the late John Paul II - the first pope to visit Greece in nearly 1,300 years. They held the landmark meeting in Athens despite vigorous protests from Orthodox zealots.
The archbishop followed up in 2006 with an historic visit to the Vatican, where he and Pope Benedict XVI signed a joint declaration calling for inter-religious dialogue and stating opposition to abortion and euthanasia.
Prime Minister Costas Karamanlis paid tribute to the bravery the archbishop showed during his sickness in a statement released Monday. Describing him as an "enlightened" cleric, Karamanlis praised Christodoulos as a "religious leader who reinforced the role of Orthodoxy in the world," and for bringing the church closer to the public.
President Karolos Papoulias expressed his sadness at news of the archbishop's death and lauded him for his "rich and multifaceted contribution" in fighting for the church.
The Patriarchate in Istanbul also issued a statement expressing its sadness at the death.
Christodoulos was born Christos Paraskevaidis in 1939 in the northeastern Greek city of Xanthi, one of two sons of a wholesale food importer and devoutly religious mother.
He grew up in Athens where was drawn to the priesthood from a young age. He was ordained at 22, and obtained degrees in law and theology from the University of Athens. His skills were soon spotted by members of the church hierarchy.
He was appointed secretary to the Church's governing Holy Synod during the 1967-74 military dictatorship. The coup leaders had installed their own church leadership under the late Archbishop Ieronymos to help realize their strictly conservative social agenda.
In a television interview years later, Christodoulos famously asserted he had been unaware of widespread abuses carried out during the dictatorship because of his demanding religious studies.
After the junta collapsed, he was elected metropolitan bishop of a diocese based in the central city of Volos, where he remained until he was elected archbishop on April 28, 1998.
Church elders turned to Christodoulos in the hopes that he could remedy years of administrative disorder under the leadership of the long-ailing Archbishop Seraphim, who had rarely appeared in public in the years leading up to his death in 1998.
In contrast to his predecessor, Christodoulos appeared on television daily, touring schools and churches, and watched his approval rating rise to 75 percent in opinion polls. He frequently weighed in on a variety of issues - in equal measure delighting the religious right and infuriating liberal and left-wing opponents.
In one of his most vociferous campaigns, Christodoulos led a petition drive against the introduction of new state identity cards that would end the practice of listing the bearer's religion. The church gathered some 3 million signatures, more than a quarter of the population.
"They are trying to take away our society's Christian and Orthodox identity, using various groundless arguments, because they hate God and want to marginalize the church," Christodoulos had said during the dispute, claiming he was fighting the "forces of evil."
The campaign ultimately failed, and Greeks' identity cards dropped the religion entry.
He was regularly named Greece's most popular public figure in opinion polls, but his abrasive tactics also made him enemies in the church and the media, who openly called for his resignation when several senior clerics were accused of embezzling funds, involvement in sexual scandals, and even trial-fixing in 2005.
Christodoulos publicly apologized for failing to contain the scandal and defeated a no-confidence motion in the Holy Synod by 67-1 votes.
During his tenure, the leader also drew criticism from politicians who accused him of meddling in their affairs, angered by his vocal opposition to everything from homosexuality and globalization to Turkey's efforts to join the European Union.
"Clergymen are above kings, prime ministers and presidents," Christodoulos once said.
He lashed out at liberals, accusing them of trying to water down Greece's strong Orthodox heritage. He proposed a Greek alternative to Valentine's Day and urged his supporters to buy Christmas cards with religious icons instead of Santa Claus and Christmas trees.
But public criticism of the church leader quickly faded after news of Christodoulos' illness spread, and prominent left-wingers visited him in the hospital.
It is unclear who will succeed Christodoulos as head of Greece's Orthodox Church. A meeting of the Holy Synod, the church's top decision-making body, was called for Monday afternoon. A decision on when elections will be held to chose a successor must be made within 20 days, Metropolitan Chrysostomos of Zakinthos said on Greek television.
Christodoulos is survived by one brother.