United Airlines is to stop flying between Belfast and New York at the start of next year.
Belfast International Airport blamed the European Commission for blocking a financial assistance package mainly coming from Stormont.
A £9 million rescue to maintain the daily route had been agreed to support Northern Ireland's only direct US link.
Airport managing director Graham Keddie claimed the Commission's decision, aimed at preventing unfair state aid, defied logic.
"You could hardly get a worse example of process-driven madness.
"To block a support package for an airline that delivers direct access to the United States is almost beyond comprehension.
"This is a vital link for business and losing it will be a body blow to Executive ministers who use it to promote Northern Ireland to would-be investors from the United States."
The United service recently carried its one millionth passenger. It will end flights on January 9.
Mr Keddie added: "The adverse impact is all the greater, coming as it does ahead of the crucial decision to make Northern Ireland more competitive with reduced corporation tax designed to stimulate inward investment.
"This is a bad day for the Executive and a bad day for Northern Ireland, which is still finding its feet after a generation lost to conflict."
Ulster Unionist MLA Steve Aiken has demanded an explanation from the region's Economy Minister and said he intends to raise the issue in the Stormont Assembly next week.
Mr Aiken said: "This is an international embarrassment. Simon Hamilton must make a statement today as we need to know how this happened.
"The Minister and his department have questions to answer over how this was allowed to happen.
"We need to know what checks were made with the European Union over state aid and who took the decision that it was not an issue?
"This is a huge blow to our international standing and the Minister must tell us what he intends to do to sort it out."
In a statement United confirmed its last flight would depart from Belfast on January 9 next year.
"We have regretfully taken this decision because of the route's poor financial performance. We will contact customers with bookings for flights beyond those dates to provide refunds and re-accommodate where possible.
"We apologise for any inconvenience caused."
However, not everyone was disappointed by the decision to block the bailout.
Green Party leader Steven Agnew said: "This decision presents us with a huge opportunity, as the money can now be used on other projects which have a much greater benefit on ordinary people's lives.
"Proposing to give the money to a large multinational airline was a vanity project from the very start, and it has now been shown to break the rules too.
"A few people may be slightly inconvenienced by having to travel a few hours down to Dublin to get a flight to New York, but if the money is now spent on better public services for everybody, such as early years' education provision, I'm sure far more people will be happy and the money will go a lot further in the long run."