The area around Sisimiut has been inhabited for several thousand years. From 2400 BC to 500 BC the area was home to the Palaeo-Inuit Saqqaq people. Later the Dorset people lived along this part of the West Greenlandic coastline until the end of the 1st century BC. Then the area remained uninhabited until the arrival of the Thule people, the ancestors of the modern Grenlandic population, in the 14th or 15th century.
The town of Sisimiut was founded as a Danish colony in 1756. Originally located on the island of Ukiivik (Sydbay) north of present-day Sisimiut, it was moved to its current location in 1764 due to changes in whaling patterns and trade possibilities. The town was named Holsteinsborg after the head of the missionary college, Count Holstein.