In the Massachusett language, missi-tuk means "large estuary", alluding to the tidal nature of the Mystic River.

The river flows from the Lower Mystic Lake and travels through East Boston, Chelsea, Charlestown, Everett, Medford, Somerville, and Arlington.

Shipbuilding peaked in the 1840s, as schooners and sloops transported timber and molasses for rum distilleries between Medford and the West Indies.

In 1950, construction was completed on the Maurice J. Tobin Bridge which spans the Mystic River, joining Charlestown and Chelsea.

In 1844, Medford abolitionist and writer Lydia Maria Child described her journey across the Mystic to her grandfather's house in the poem "Over the River and Through the Wood."

John Townsend Trowbridge's popular 1882 novel, The Tinkham Brothers' Tide-Mill, had its setting along the river at a time when saltwater still reached the Mystic Lakes.

In Dennis Lehane's novel of the same name, Boston-area Mystic River holds a pivotal narrative development in the mystery.