The US has barred American-registered aircraft from flying over Iranian airspace in the Persian Gulf and the Gulf of Oman, with other major airlines following suit.
The US flight ban was implemented over Iran's Revolutionary Guard shooting down a US military surveillance drone, affecting a region crucial to global air travel.
The Federal Aviation Administration warned of a "potential for miscalculation or misidentification" in the region after an Iranian surface-to-air missile on Thursday brought down a US Navy RQ-4A Global Hawk, an unmanned aircraft with a wingspan larger than a Boeing 737 jetliner and costing over US$100 million ($152 million).
The US said it made plans for limited strikes on Iran in response, but then called them off.
The FAA previously warned of a risk in the region, but Friday's warning threw into stark relief a danger both it and analysts warned was real after the shooting down of a Malaysian Airlines flight over Ukraine in 2014.
"The threat of a civil aircraft shoot-down in southern Iran is real," warned OPSGROUP, a company that provides guidance to global airlines.
The FAA made a similar warning in May to commercial airliners of the possibility of Iranian anti-aircraft gunners mistaking them for military aircraft, something dismissed by Tehran some 30 years after the US Navy shot down an Iranian passenger jet.
Iran had no immediate reaction to the US announcement.
Major airlines implement no-fly zone
British Airways, Australian commercial airline Qantas and Dutch carrier KLM said its planes will not fly over Strait of Hormuz.
Qantas said it would affect its flights between Australia and London.
It stressed its flights pass over the region at 40,000 feet.
Abu Dhabi-based long-haul carrier Etihad says it has "contingency plans" after the US barred American-registered planes from flying through Iranian-administered airspace in the Persian Gulf and the Gulf of Oman.
KLM said in a brief statement that the "incident with the drone is reason not to fly over the Strait of Hormuz for the time being."
KLM said the move is a "precautionary measure."
German airline Lufthansa also said it won't fly over Strait of Hormuz, Gulf of Oman, in the wake of the US drone shooting down.
The FAA said its warning would affect the area of the Tehran Flight Information Region, without elaborating.
That area probably only extends about 20km off of the Iranian coast, aviation experts said.
There are "heightened military activities and increased political tensions in the region, which present an inadvertent risk to US civil aviation operations and potential for miscalculation or misidentification," the FAA said.
"The risk to US civil aviation is demonstrated by the Iranian surface-to-air missile shoot-down of a US unmanned aircraft system on 19 June 2019 while it was operating in the vicinity of civil air routes above the Gulf of Oman."
The Persian Gulf is home to some of the world's top long-haul carriers, who already have been battered by Trump's travel bans targeting a group of predominantly Muslim countries, as well as an earlier ban on laptops in airplane cabins for Mideast carriers.