Isabella Macdonald, née Clark (1811 – 1857) was the first wife of John A. Macdonald, the premier of the Province of Canada in 1856. She was Macdonald's first cousin.
She became ill after just two years of marriage, and died in 1857. Medical examinations concluded that she was suffering from a somatization disease. She had also developed an addiction to opium mixed with wine.
After Clark's death, Macdonald went on to become the first post-Confederation Prime Minister of Canada. He remarried to Susan Agnes Bernard in 1867, five months before Canadian Confederation.
Macdonald and Clark had two sons: John and Hugh; the former died at 13 months.