A few short months later, Isabella married her husband's close friend Colonel John C. Greenway, also a Rough Rider whom she had met and fell in love with in 1911. Less than a year later, having moved to Ajo, Arizona, Isabella gave birth to her third child, John Selmes Greenway.

In 1923, after only two years of marriage, Isabella's husband died leaving her a widow once again. But despite her grief, she endured and began buying ranch land in 1927, eventually acquiring over 130,000 acres, as well as several lots in the heart of