The 52-year-old man collided with a Land Rover near Creetown, five miles east of Newton Stewart.
The crash has closed the main Euro-route from the ferry ports at Cairnryan to the UK motorway network.
Diversions have been set up through Carsluith village but Police Scotland warned drivers that there will be delays.
The accident happened just before 12:00 on the Carsluith bypass.
The man who was driving the Land Rover and his female passenger escaped with only shock and bruising.
A woman who lives nearby said: "We just heard an almighty bang and then a woman came in asking us to call the emergency services.
"The diversion is right past our houses here in the village and it's the second time in successive weeks that the road has been closed for hours.
She added: "Last week it was three lorries that were involved in a crash and the road was closed for 18 hours."
A Police Scotland spokesman said: "We received the call about 11.40pm and the motor cyclist has died from the results of the accident. The other two people in the Land Rover were not badly hurt.
"The road remains closed in both directions as an accident investigation goes on."
A motorbike rider has died in a crash on the A75 Gretna to Stranraer road in Dumfries and Galloway.