Archbishop of New York Cardinal Timothy Dolan arrived on the first chartered transatlantic flight to land in Knock in the airport's 30 years in operation.
The Aer Lingus flight, with 178 pilgrims on board, landed at 8.30am yesterday and was greeted by a host of political representatives including Taoiseach Enda Kenny.
"There is no reason why Knock cannot stand on the pedestal of the great Marian Shrines of the world such as Lourdes or Fatima," said Mr Kenny. "This day is one of exceptional importance for the people of the west of Ireland, and we welcome our visitors with open arms."
The transatlantic initiative was championed by the Rector at Knock Shrine, Fr Richard Gibbons, and by Car- dinal Dolan, who led the pilgrimage from JFK airport.
"We hope and pray this will be the first such trip of many from New York to Knock," said Cardinal Dolan.
"We are so honoured to be part of this historic visit and will spread the word in America about what this beautiful part of Ireland has to offer."
Irish musicians played for the pilgrims on arrival and local people turned out in big numbers to welcome them. Many were visiting Ireland for the first time.
In Knock village, red, white and blue ribbons were tied to trees and lamp-posts and Vatican flags hung from windows.
Also on board the flight was Papal Nuncio to Ireland, Archbishop Charles John Brown, who is from New York.
Knock Shrine receives around 1.6 million visitors a year, and those involved in managing it hope further flights from abroad could see that figure grow to at least three million in the coming years.
After a welcoming reception at the airport, the pilgrims visited the renovated Knock Shrine Basilica where Cardinal Dolan celebrated mass with RTE broadcasting the event live.
The cardinal will officially launch the 2015 National Novena in Knock on Friday.
It is expected to attract up to 150,000 people over the nine days.