In 1832, he was appointed assistant political agent at Ludhiana and in that capacity accompanied Claude Martin Wade on a Mission to Lahore and Bahawalpur in connection with the Indus navigation scheme.

He remained in Peshawar throughout the First Anglo-Afghan War responsible for forwarding supplies and money to Sir Robert Sale in Jalalabad, hastening up reinforcements and maintaining British influence in the Khyber region.

[3] Mackeson's reputation was enhanced by the war, and a colleague Henry Lawrence described him as an "excellent officer, first-rate linguist, a man of such temper that no native would disturb and of untiring energy" he noted that "his life was spent in discoursing night and day with false Sikhs and Khyberees at Peshawar, and treading almost alone, or attended by Afghan escort, the paths of the Khyber".

[5] However, after the war when the prestigious position of British Resident to Lahore became available, he was overlooked in favour of Henry Lawrence, who lacked Mackeson's first hand frontier experience.

For the next two years Mackeson was asked to pacify the frontier tribes, amid fears that subversive Wahhabi agents had been supporting local insurrection.

[13] The Government assembled an expeditionary force under Mackeson's command, including columns led by Robert Napier and James Abbott, which successfully retook the forts.

On 10 September 1853 while listening to appeals in his veranda, he was greeted with a low salaam and presented with a piece of paper by a religious fanatic from Swat who proceeded to stab him with a large knife.