Chalmers was educated at St. Andrews University (beginning at age 11) became both minister at Kilmeny and a science lecturer at the university. In 1815 he became minister at the Tron parish church in Glasgow. In the new industrial society, education, social care and charity with self-help were part of his Christian doctrine. He reorganised parochial poor relief and established schools and district churches. Chalmers was a prolific writer and preaching on occasions in London brought him additional fame. In 1823 he was appointed to the chair of Moral Philosophy at St Andrews University and in 1838 he became professor of theology at the University of Edinburgh.

A campaign against patronage and the influence of wealthy parishioners in the church led to the so-called Disruption of 1843 in which he led a third of the ministers out of the established church to create the "Free Church of Scotland". It was funded by every church member paying one penny a week to the local church. Thanks to Chalmers' planning and organizational ability, nearly every presbytery had a minister of the new church as an alternative to the established kirk. The Free Church was particularly strong in the Highlands, where its strict religious principles are still felt to this day.

Chalmers became the first Moderator of the new church. The ministers who had walked out were left without a church or a manse but within two years 500 churches had been built as well as schools, since supportive schoolmasters (appointed by the local church) had been driven out as well. Chalmers died in 1847 but not before he had seen the successful creation of the new church.