Isabelle Clark was born in Dalnavert in Inverness-shire, Scotland, to parents Alexander and Margaret Clark. She met her husband to be, her half-cousin John Alexander Macdonald, while he was in Great Britain in 1842. The visit included a trip to Douglas on the Isle of Man to see his cousin Margaret Greene née Clark who lived in a small farmhouse near Douglas together with her sister Isabella. Macdonald took an immediate liking to Isabella, suggesting she should visit Kingston the following year, ostensibly to see another of her sisters, Maria, who had married John Alexander Macpherson. Isabella complied, sailing to Canada in 1843 to visit the Macphersons in Kingston, Ontario, as well as the Macdonalds. It was on this trip that after a few months courting, they were engaged and finally married on September 1, 1843, in St. Andrews Church, Kingston. The couple were related by sharing their maternal grandmother; cousin marriage was not uncommon at the time. They lived together in Kingston. Although the marriage got off to a good start, Isabella realized her husband's main interests were Business and politics.