During the 1880s and 1890s, in addition to his pioneering work at Domasi, Hetherwick also had significant responsibilities in the leadership of Blantyre Mission as a whole. He quickly established himself as the right-hand man of David Clement Scott, the inspirational leader of the Mission, and acted as deputy for Scott during the latter's sometimes lengthy furloughs. Indeed, in the perception of both friend and foe, the two men came to be regarded, for practical purposes, as a single unit. This applied equally to the missionaries, such as John McIlwain or Janet Beck, who were devoted and loyal to their leadership and to those, such as R. S. Hynde or George Robertson, who became fiercely opposed to it. Likewise, in the wider community it was recognised that Scott and Hetherwick were a ‘double-act’. When they adopted a critical attitude to some of the policies of the British administration during its early years in the 1890s, the two were regarded equally as a thorn in the side, one as bad as the other. Therefore, during the 1880s and 1890s, in addition to his particular responsibility for the Domasi station, Hetherwick was a major player in the overall leadership of the Mission, albeit at this point he was the ‘right-hand man’ rather than the principal. When Scott left Blantyre in early 1898, it was obvious to everyone that Hetherwick would be his successor and, in many ways, he simply carried on with what he had already been doing as the close associate and deputy of Scott.

Those close to Blantyre Mission were in no doubt in 1898 that it had lost a brilliant and inspiring leader, even if the bright light had dimmed somewhat since 1895 when both his wife and brother died in the same month while at the same time the campaign against him and Hetherwick for alleged ‘ritualism’ was reaching a crescendo in Scotland. On Scott's departure the Mission's staff and supporters were reassured that Hetherwick was perfectly placed to step into his shoes so that the Mission would continue on the lines that by then were well established. Subsequent scholarship, however, has suggested that there was a wide difference between the two. In his authoritative history of the early history of Blantyre Mission, Andrew Ross argued that Scott's departure in 1898 marked a profound change in the life and policy of the Mission.