Although its meaning is unknown, the origin of the word "Tomifobia" is likely Algonquin, the language spoken by the Abenaki tribes that
seasonally travelled on the lake and river systems of the Eastern
Townships prior to European settlement. An important link between the Connecticut and Saint Lawrence basins, the Tomifobia River is one of the most southern rivers to flow northward and eventually drain into the Saint Lawrence (via the Saint Francis).

The Abenaki allied themselves with France during the French and Indian Wars and the Tomifobia valley remained part of New France until the 1763 Treaty of Paris, which granted the region to the English. Cited on maps as the "Barlow River"prior to 1900, the Tomifobia River valley was settled by United Empire Loyalists in the late 18th-century soon after the Constitutional Act of1791 opened the land of what was then Lower Canada. Significant communities developed around a series of mills that were built on the river in the early part of the 19th-century , leading to the establishment of Boynton, Tomifobia [formerly Smith's Mills], and Stanstead Plain [Kilborn's Mills]. Each of these villages would soon become stops along an important stagecoach and later railroad route between Boston and Montreal (the Massawippi Valley Railroad became part of the Boston and Maine Railroad network in 1867).

Today the Tomifobia River runs through an area that is mostly
provincially protected Green Zone within the counties of Canton de
Stanstead, Stanstead-est, and Ogden. This has helped protect the river from heavy waterfront housing growth (except near Lake Massawippi in Ayer's Cliff), characteristic of a number of other bodies of water in the area. While a study by Roberge & Roy (2004) suggests there is little continuously suspended sediment in the river, there are some concerns about the expansion of the Tomifobia delta at the mouth of Lake Massawippi. Research indicates that this delta has been built through sporadic hydrological events rather than through agricultural catchment. Nevertheless, agricultural practices have undoubtedly contributed to the high levels of phosphates detected in lower portions of the river following periods of heavy rainfall.