The 1715 Jacobite rising had prompted London to fortify the line that became, a century later, the route of the Caledonian Canal. The chain ran from Inverness Castle and Fort George in the north, through Fort Augustus in the middle, to Fort William at the south end of the Great Glen. When the 1745 rising began, the garrisons were strengthened but the defences had been neglected. It was not until February 1746, after the Jacobites abandoned the siege of Stirling Castle, that they turned seriously to reducing the Highland forts. Blair Castle fell. Fort Augustus surrendered on 1 March. Fort William, the last, was next.

Fort William was triangular, designed to use the head of Loch Linnhe as natural cover, with six 12-pounder cannon, eight 6-pounders, seven smaller pieces, two 13-inch mortars and eight coehorns. The garrison numbered around 400, drawn from Guise's Regiment, Johnson's Regiment and the Campbell of Argyll Militia. Offshore lay the sloop of war HMS Baltimore and the bomb vessel Serpent, both ready to land raiding parties and put fire on the surrounding shore. The fort's one weakness was a lack of permanent water supply. On 25 February the garrison demolished the village of Maryburgh just outside the walls to clear a field of fire. The current governor, Alexander Campbell, was replaced on 15 March by Captain Caroline Frederick Scott, who arrived aboard Serpent and proved a more aggressive commander.

Colonel Stapleton arrived outside the fort with 150 French regulars on 8 March, supported by Lochiel's Camerons and MacDonald of Keppoch's clansmen. Heavy guns sat stranded at Inverness, no horses available to haul them west; only light artillery and mortars reached the siege lines. The Jacobite engineer Grant was wounded by counter-battery fire and replaced by Mirabel de Gordon, whose performance at Stirling had been so poor some suspected bribery. The Jacobites opened fire on 20 March. Their batteries on Sugar Loaf Hill and Cow Hill turned out to be poorly sited. Scott's counter-battery fire was effective, and moonlit nights kept the besiegers from working under cover. On 28 March the Jacobites fired heated shot, grapeshot, old nails and red-hot iron rods at the upper works, damaging the roof but not the structure. On the night of 31 March, Scott sent 150 men out to spike four 6-inch mortars and three 4-pounder cannon.

The siege had achieved nothing. The walls held. The Royal Navy controlled the loch. The Camerons and MacDonalds, frustrated at being unable to defend their own lands while tied down at Fort William, quarrelled with each other and with the French regulars who did most of the digging. With Cumberland's army leaving Aberdeen, Prince Charles needed every man. The Jacobites were ordered back to Inverness. On 3 April the garrison woke to find the besiegers gone, abandoning guns and heavy equipment in their haste. Two weeks later, on 16 April, the Jacobite army was destroyed on Culloden Moor. Captain Scott went on to lead the brutal post-Culloden search for Prince Charles, then transferred to the East India Company in 1752 and died of fever in Calcutta. The fort itself was manned until 1854, decommissioned a decade later, and finally sold to the West Highland Railway.