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The regiment is notable for the massacre inflicted on it after the Fall of Fort William Henry during the French and Indian War, as depicted by James Fenimore Cooper in his book Last of the Mohicans and in the movie of the same name.

The 35th Foot was part of the garrison, under Lieutenant-Colonel George Monro in August 1757 when it was forced to surrender to the superior forces of General Montcalm. The force was allowed to leave the fort with their weapons. The Native American allies of the French set upon the retreating force killing 185 and turning the retreat into disorder, with many members of the garrison being lost in the wilderness for a number of days before reaching safety.

In 1759 the regiment had its revenge on Montcalm when, at the Battle of Quebec (1759), the 35th Foot were in General Wolfe's army on the right of the British line. The steady fire of the 35th broke the French Regiment Royal Roussillon, which had been at Fort William Henry, who turned and fled. Regimental tradition states that members of the regiment picked up the Frenchmen's plumes and placed them in their own headresses. The Roussillon Plume would be incorporated into the badge of the Royal Sussex Regiment in 1881.

The regiment was also involved in the Expulsion of the Acadians, participating in the Cape Sable Campaign and the Petitcodiac Campaign.