There was no firm evidence of the man's death but "we've lost contact with him and his family has lost contact with him", the Prime Minister said.
"We haven't had any evidence since January that the person's alive and on that basis there is a reasonably high probability the person's died."
Mr Key would not reveal what forms of contact the Government had with the expat New Zealander.
Details about the rebel fighter were scarce. He spent some time in New Zealand but may have departed to the Middle East from Australia.
A "handful" of New Zealanders were believed to be fighting in the Middle East, said Mr Key, and others had been blocked from going there by having their passports cancelled under national security provisions. He said if any of these people returned to New Zealand they could be monitored.
The man killed in Syria had no known connection to another New Zealander, Daryl Jones, who was killed by a drone strike in Yemen in November after joining an al-Qaeda terror cell. Australian media last week claimed another man killed in that drone strike, Australian Christopher Harvard, met Jones at a Christchurch mosque, where he was radicalised.
Asked to respond to these allegations of radical preaching in New Zealand, Mr Key said intelligence authorities targeted individuals, not mosques.
"It doesn't happen because we have a feeling, it happens because we have very strong information which would support a warrant being authorised. And then that warrant has to be co-signed by the commissioner and myself. So we don't just get up in the morning and say 'maybe in this location we might be a bit worried so let's have a look'."
NZ deaths in conflict
*Daryl Jones: Also known as Muslim bin John, Jones was killed by a drone strike in Yemen in November after joining an al-Qaeda group and attending a training camp. New Zealand spy agencies may have contributed information which led to the drone strike. His death was confirmed by DNA evidence.
*Unidentified man: Believed to have been killed in Syria while fighting against Bashar al-Assad's regime. Lived in New Zealand at some point, but may have left for the Middle East from Australia.