He was killed at the Battle of Culloden leading a regiment composed largely of members of his clan, the MacDonalds of Keppoch (Scottish Gaelic: Clann Dòmhnaill na Ceapaich).

Alexander's father had used the 1689 Jacobite rising to further his local grievances; the questionable legal status of the Keppoch estates, ostensibly held on a lease from the chiefs of Clan Mackintosh, had been recognised by the government for many years as one of the main sources of political instability in the western Highlands.

A posthumous portrait exists, dated 1765 and possibly taken from an earlier miniature;[1] a source from the time of the 1745 rising described "old Keppoch" as a "Man of an austere aspect, tall, lusty and strong, much inur'd to War, and can endure any Hardships".

Scottish Jacobites were dismayed when Charles arrived in Scotland without the French support they had requested; most tried to persuade him to leave, but the commitment of Keppoch and Donald Cameron of Lochiel in the first weeks of August made the rising viable.

[11] Although the regiment had a strength of 300 when Charles's standard was raised at Glenfinnan, many of the men deserted a few days later due a "private quarrel" between them and their chief, allegedly because the devoutly Protestant Keppoch refused to allow a priest to accompany his Catholic tenants.

[14] Keppoch's men, led by his cousin, Maj. Donald Macdonald of Tirnadris, were involved in the first skirmish of the Rising when they ambushed Captain John Scott's soldiers at Highbridge near Fort William on 16 August.

[15] Keppoch and his regiment subsequently took part in the advance south to England, were involved in the night action at Clifton on 18 December,[15] and later, brought up to a strength of around 500, played a significant role in the Battle of Falkirk Muir.

His colleague James Johnstone called him a "gentleman of uncommon merit and [...] universally lamented",[21] whereas a 1746 pamphlet describing the trial of his nephew Donald said that "he is a man dreaded, but not beloved", adding that he "slept in the open fields in his Plaid" during the rising.