The name Nakhon Phanom, meaning "city of mountains", was given to the city by King Rama I. There are no mountains within Nakhon Phanom itself, the limestone mountains being concentrated in the city of Thakhek in Laos on the other side of the Mekong River. Nakhon Phanom is more accurately described as a city where the mountains can be seen.
The area had been long settled by Lao people and belonged to the Lan Xang kingdom. After it came under the control of the Kingdom of Ayutthaya, the population remained predominantly Lao speaking. At first it was known as Si Kotrabun, and during the reign of King Rama I was called Maruka Nakhon.