At the time of the Sepoy Rebellion of 1857, Brydon was still serving as a surgeon of the Bengal Army. Stationed in Lucknow along with his wife and children, Brydon survived his second siege; that of the Lucknow residency (June – November 1857), in which he was badly wounded in the thigh. He was appointed a Companion of the Order of the Bath (CB) in November 1858. His wife, Colina Maxwell Brydon, published a memoir of the siege.