In 1750, Isabelle was sent to Geneva and travelled through Switzerland and France. Having spoken only French for a year, she had to relearn Dutch on returning home to the Netherlands. However, French would remain her preferred language for the rest of her life, which helps to explain why, for a long time, her work was not as well known in her country of birth as it otherwise might have been.
Isabelle enjoyed a much broader education than was usual for girls at that time, thanks to the liberal views of her parents who also let her study subjects like mathematics. By all accounts, she was a gifted student.
As she grew older, various suitors appeared on the scene only to be rejected. She saw marriage as a way to gain freedom but she also wanted to marry for love. Eventually, in 1771, she married Charles-Emmanuel de Charrière de Penthaz, her brothers' former tutor. They settled at Le Pontet in Colombier (near Neuchâtel) in Switzerland. They also spent significant amounts of time in Neuchâtel, Geneva and Paris.
In 1760, Isabelle met David Louis de Constant d'Hermenches (1722 - 1785), a married Swiss officer who society regarded as a Don Juan. After much hesitation, Isabelle's need for self-expression overwon her scrupules and she started an intimate and secret correspondence with him after a second meeting with him two years later. Constant d'Hermenches would be one of, if not her most, important correspondents.
The Scottish writer James Boswell was a frequent visitor to Castle Zuylen in 1762 and became a regular correspondent after leaving the Netherlands. He proposed to her and she refused, saying she had "no talent for subordination".
In 1786, Mme de Charrière met Constant d'Hermenches' nephew, the writer Benjamin Constant. They began an exchange of letters that would last until the end of her life.
Her first novel, Le Noble, was published in 1762. It was a satire against the nobility and although it was published anonymously, her identity was soon discovered and her parents withdrew the work from sale.
In 1784, she published two novels, Lettres neuchâteloises and Lettres de Mistriss Henley publiée par son amie. Both were epistolaries, a form she continued to favour. In 1788, she published her first pamphlets about the political situation in the Netherlands.
As a great admirer of the philosopher Jean-Jacques Rousseau, she assisted in the posthumous publication of his work, Confessions, in 1789. She also wrote her own pamphlets on Rousseau around this time.
The French Revolution caused a number of nobles to flee to Neuchâtel and Mme de Charrière befriended some of them. But she also published works criticising the attitudes of the noble refugees, most of whom she felt had learned nothing from the Revolution. However, she wasn't an outright democrat either, looking with dismay on the violence of the revolutionary mobs.